Chelation and Stereodirecting Group Effects on Regio- And Diastereoselective Samarium(II)-Water Allylic Benzoate Reductions

SYNTHESIS

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T. F. Stockdale et al.

Paper

Synthesis

Chelation and Stereodirecting Group Effects on Regio- and

Diastereoselective Samarium(II)-Water Allylic Benzoate

Reductions

Trevor F. Stockdale

Michael A. Leitch

Gregory W. O’Neil*

stereodirecting group

H

O

H

O

R

OH

OBz

R

SmI₂

H₂O

( )_x( )_y

• 13 examples

• high yields (up to 90%)

• up to 90:10 d.r.

H

Sm

Ph

( )_y

*

OH

( )_x( )_y

Ph

( )_x

R

chelating group

Ph

Department of Chemistry, Western Washington University,

516 High Street, Bellingham, WA 98225, USA

oneilg@wwu.edu

x, y = 0–2

• complete regioselectivity

Received: 31.12.2019

Accepted after revision: 28.01.2020

Published online: 20.02.2020

Our group became interested in the use of SmI₂for the

reduction of acyloxysulfones as part of a masked-alkene

metathesis protocol.¹¹More recently we reported that allyl-

ic benzoates 1a or 1b can be reduced with SmI₂in the pres-

ence of an alcohol additive (R′OH),¹²converging to the cor-

responding reduced products 2 with high regioselectivity

(Scheme 1). The regioselectivity of this reaction can be ra-

tionalized by steric considerations of the organosamarium

intermediate, and a pericyclic protonation mechanism in-

volving a samarium-bound alcohol molecule. This method

then featured in our synthesis of the biologically active nat-

ural product honokiol to simultaneously install both allyl

substituents found in the target compound from the bis-

allylic benzoate precursor 3.¹³

DOI: 10.1055/s-0039-1690826; Art ID: ss-2019-n0518-op

Abstract SmI₂(H₂O)_nreductions of allylic benzoates adjacent to a tri-

substituted alkene occur in high yields with complete regioselectivity

and good diastereoselectivity (up to 90:10) for substrates containing

properly positioned stereodirecting- and chelating groups. The out-

come of these reactions can be rationalized by ring conformation con-

siderations of a proposed chelated organosamarium intermediate, and

a mechanism involving intramolecular protonation by a samarium-

bound water.

Key words samarium, reduction, diastereoselective, regioselective,

chelation

Since its introduction more than 40 years ago,¹samari-

um(II) iodide (SmI₂) has proven to be an extremely useful

and versatile reductant available to the synthetic chemist.²

Much of this success relies on the use of certain additives,

which change the coordination sphere and redox potential

of the reagent,³allowing for the selective and efficient re-

duction of a wide range of functional groups. Among the

additives commonly employed, proton donors are of special

interest.⁴In particular, the addition of water to SmI₂[often

represented as SmI₂(H₂O)_n] has been shown to have a sig-

nificant impact on its reducing capability,⁵enabling for in-

stance the reduction of carboxylic acid derivatives⁶while

avoiding the use of toxic and/or less green additives like

HMPA, DMPU, or TPPA.^3b,7A number of investigations have

been conducted to understand the special role of water in

these transformations that have revealed higher redox po-

tentials⁸and rate enhancements for water relative to other

proton sources (e.g., methanol).⁹Recent studies indicate

that the mechanism for many of these processes may in-

volve both concerted and asynchronous proton-coupled

electron-transfer.¹⁰

A) SmI₂reduction of 1a or 1b and origin of selectivity for forming 2.

OBz

R'

O

Ph

R

SmL_n

H

SmL_n

R

SmI₂

R'OH

1a

or

Ph

R

Ph

R

Ph

OBz

R

2

Ph

1b

B) Application of SmI₂allylic benzoate reduction to the synthesis of honokiol.

OP

SmI₂, MeOH

(98%)

OBz

honokiol; P = H

3

OBz

Scheme 1 (A) Regioselective SmI₂allyl benzoate reductions and (B) its

application to a synthesis of honokiol

Applied to trisubstituted alkene-containing substrates,

we recognized that the reaction would generate a new ste-

reocenter (*), and became interested in finding ways to de-

velop this reaction as a new strategy for stereoselective syn-

thesis (Scheme 2).¹⁴We hypothesized that incorporation of

a Lewis basic chelating element (e.g., OP) and stereo-

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B

T. F. Stockdale et al.

Paper

Synthesis

directing group (R) would render SmI₂(H₂O)_nreductions of

compounds of type 4 both regio- and diastereoselective. To-

gether, these groups could impart facial selectivity during

the intramolecular protonation event from a chelated inter-

mediate. The importance of chelation to our design was

supported by the reduction of compound 5 to product 6,

which proved to be non-diastereoselective.

as a result of greater chelation to samarium,¹⁹although sec-

ondary coordination sphere effects (e.g., hydrogen-bond

networks) cannot be ruled out at this time (Scheme 4, Table

1).^8,10aThe impact of different additives on the outcome of

the reaction with 12 were investigated as outlined in Table

1. Interestingly, the highest (and nearly identical) diastereo-

selectivities were obtained using either anhydrous condi-

tions (DMPU; entry 1) followed by quenching (aq NH₄Cl) or

in the presence of water (entry 5),²⁰suggestive against an

internal protonation by the hydroxyl group per se (per-

forming the reaction in D₂O resulted in >90% deuterium in-

corporation by ¹H NMR at C5). Both reactions produced

compound 13 as a 3:1 mixture of diastereomers and exclu-

sively as the trans-isomer, however, regioselectivity for the

DMPU reaction was much lower (2:1 vs 15:1 for H₂O). Cold-

er conditions (i.e., 0 °C, entry 6) also led to an erosion of re-

gioselectivity. The reaction proved non-stereospecific to the

stereochemistry of the OBz stereocenter, with identical re-

sults obtained when 12 was used as a 50:50 (entry 7) or

70:30 (entry 5, ref. Scheme 3) mixture of diastereomers.²¹

This is attractive from a synthetic standpoint, allowing us to

prepare and use substrates epimeric at this position with-

out any impact on the subsequent reductions. The amount

of water used also had little effect on the d.r. of the reac-

tions [e.g., 76:24 for 70 equiv (entry 8) vs 75:25 for 1400

equiv (entry 6)], consistent with other studies showing that

even high concentrations of water do not lead to complete

saturation of Sm(II).^3bRegioselectivity, however, tended to

be higher at fewer equivalents of H₂O, perhaps as a result of

a competing intermolecular protonation at the higher

equivalents (ref. Scheme 1). Yields also increased with de-

creased H₂O [with the exception of 1 equiv (66% yield)],

where side-products that we have tentatively assigned as

radical dimers were observed.²²The absolute configuration

of the newly formed stereocenter was determined by ozo-

nolysis of 13 and comparison of the optical activity of the

resulting aldehyde 15 to that previously reported.²³This

analysis revealed that the sample was enriched in the (S)-

(+)-enantiomer, indicating that the major diastereomer of

13 had the (2R,5R)-configuration. Our working model to ex-

plain the stereochemical outcome of this reaction is based

on the ring-conformation energetics of a fused 5,6-bicyclic

organosamarium transition state structure Sm-I,²⁴involv-

ing hydroxyl chelation of samarium²⁵followed by intra-

molecular protonation by a coordinated water molecule.

R

chelation

Sm OP

( )_n

diastereo-

selective

Y

OBz OP

( )_n

Y

*

OP

( )_n

O

SmI₂

ROH

H

A)

B)

Y

X

protonation?

4

R

OBz

SmI₂

ROH

Ph

*

Ph

5

non-chelating groups

6 (d.r. 1:1)

Scheme 2 (A) Proposed regio- and diastereoselective allylic benzoate

reductions proceeding through a chelated organosamarium intermedi-

ate. (B) The importance of chelation for stereoselectivity is supported

by the non-diastereoselective reaction of compound 5, which lacks this

ability.

For the chelating element we chose to focus on oxygen

given the well-established oxophilicity of samarium.¹⁵This

also introduced an obvious synthetic disconnection (i.e., a

carbonyl addition) when designing the synthesis of our de-

sired substrates. With these considerations in mind, initial

investigations began with the preparation of compound 8

by zirconium-catalyzed carboalumination¹⁶of phenyacety-

lene and addition of the resulting vinylalane into Roche

ester-derived aldehyde (S)-7¹⁷(Scheme 3). The stere-

ochemistry of the newly formed hydroxyl in 8 for the major

isomer is assumed to be (S) arising from chelation control,¹⁸

but was not rigorously determined as this stereocenter

proved unimportant for the subsequent eliminations (vide

infra). After benzoylation, unfortunately the reduction of 9

in the presence of various additives proceeded with low

diastereoselectivity (50:50 to 60:40) and only modest

regioselectivity (up to 5:1).

OH

AlMe₃, Cp₂ZrCl₂

BzCl, pyr.

Ph

OPMB

OHC

then

(quant.)

OPMB

8

(85%, d.r. 70:30)

7

OBz OPMB

PMBO

SmI₂

+

Ph

(see Table)

9

10

11

Entry Additive^a10:11^b10 d.r.^b

Notes: ^aReactions were performed by

adding the additive (16 equiv DMPU or

1400 equiv ROH) to SmI₂(7 equiv)

followed by the substrate at room

temperature. ^bDetermined by NMR.

1

OBz OH

OH

DMPU

t-BuOH

MeOH

H₂O

1.3:1

3:1

60:40

69:31

60:40

50:50

SmI₂

2

3

4

+

Ph

3:1

5:1

conditions

12

(R,R)-13

14

(see Table 1)

(d.r. 70:30)

H

via

O₃then

Me₂S

CH₃

OH

D

Scheme 3 Synthesis of substrate 9 and initial screening of its reduc-

tion with SmI₂(H₂O)_nin the presence of various additives

SmI₂

H

CH₃

12

O

D₂O Ph

5

Sm

Ph

CH₃

O

H

Ph

O

Gratifyingly after PMB-removal, reduction of the corre-

sponding free hydroxyl compound 12 proceeded with both

enhanced regio- and diastereoselectivity (d.r.), presumably

(+)-15

Sm-I

Scheme 4 SmI₂reduction of compound 12 and determination of ab-

solute stereochemistry by ozonolysis of 13

C

T. F. Stockdale et al.

Paper

Synthesis

Table 1 Additive Effects on SmI₂Reductions of Compound 12 (ref.

Scheme 4)

OH

AlMe₃, Cp₂ZrCl₂

1. BzCl, pyr.

2. DDQ

R

OPMB

OHC

then

OPMB

R

16

R = Ph, 17, 82% (d.r. 58:42)

R = n-Bu, 18, 58% (d.r. 56:44)

Entry

Additive^a

13:14^b

d.r.^bof 13

OBz

SmI₂/H₂O

1

2

3

4

5

6

7

8

DMPU

t-BuOH

i-PrOH

MeOH

H₂O

2:1

1:0^c

2.3:1

1:0^c

15:1

5:1

75:25

67:33

60:40

76:24

75:25

76:24

OH

R

see Table

R = Ph, 21

R = n-Bu, 22

R = Ph, 19, 80%

R = n-Bu, 20, 89%

O₃

O

Ph

21

then DMS

(S)-(+)-15

H₂O

Isolated

yield

R

(equiv)

d.r.

via

H

Ph

n-Bu

5

86:14

84:16

90:10

88:12

53

60

50

55

H

O

H₂O^d

CH₃

H

O

100

200

50

Sm

H

H₂O^e

15:1

R

Sm-II

n-Bu 100

H₂O^f

^aReactions were performed by adding the additive (16 equiv DMPU or

1400 equiv ROH) to SmI₂(7 equiv) followed by the substrate and stirring for

30 min.

Scheme 5 Synthesis and elimination of lactate-derived compounds 21

and 22

^bDetermined by ¹H NMR spectroscopy.

^cCompound 14 was not detected by NMR spectroscopy.

^dPerformed at 0 °C.

yl groups three and four carbons away (as opposed to one

and two carbons for compounds 19 and 12, respectively)

from the allylic benzoate position (Scheme 6). The reduc-

tion of 25 proceeded with comparable diastereoselectivity

(78:22) to compound 12, giving 26 via a mechanism pre-

sumably involving the 6-membered chelate Sm-III. The

methyl group in Sm-III assumes a preferred equatorial con-

formation, controlling the facial selectivity of the protona-

tion event and explaining the stereochemistry observed in

the final product. It was anticipated that the reaction of

compound 30 would give lower selectivity as the 7-membered

^eCompound 12 was used as a 1:1 mixture of diastereomers.

^fPerformed using 70 equiv of H₂O.

In thinking about other suitable and available aldehyde

starting materials from which we could prepare additional

substrates to further investigate this transformation, we

were drawn to lactate-derived aldehyde 16²⁶(Scheme 5).

Using similar chemistry to that employed in the synthesis

of 12, we prepared compounds 19 and 20 and investigated

their reduction with SmI₂(H₂O)_n. Treatment of 19 or 20 to

our optimized conditions from experiments with 12 (e.g.,

15 equiv H₂O relative to SmI₂, r.t.) gave the desired products

21 or 22 with complete regioselectivity and high diastereo-

selectivity [84:16; higher than for compound 12 (75:25)],

however, in low yield due to a competing elimination and

formation of the corresponding diene (presumably -elimi-

nation of the hydroxyl group after benzoate cleavage). In-

creasing the equivalents of water to either 100 or 200

equivalents suppressed this elimination to some extent

(presumably by increasing the rate of protonation), allow-

ing for the isolation of 21 in 60% yield. The highest d.r.

(90:10) was obtained for the n-butyl substrate 20 using 50

equivalents of water, giving compound 22 in 50% isolated

yield. The absolute configuration of the newly formed ste-

reocenter was determined by ozonolysis of the product

which produced primarily (S)-(+)-aldehyde 15 by polarime-

try.²³A possible model to explain this selectivity based on

that previously proposed for the one-carbon homologated

samarium intermediate is shown in Scheme 5, with the or-

ganosamarium transition state structure Sm-II existing in

this case as an η³-complex.²⁷

A) Synthesis and reduction of 25 through a 6-membered chelate Sm-III.

OH

AlMe₃, Cp₂ZrCl₂

1. BzCl, pyr.

2. DDQ

Ph

then

OHC

OPMB

24

(65%, d.r. 60:40)

preferred equatorial

OPMB

23

H

OBz

CH₃

Ph

SmI₂

H₂O

Ph

Sm

HO

H

HO

26

HO

Sm-III

25

CH₃

(d.r. 78:22)

(86%, 2 steps)

B) Synthesis and reduction of 26 through a 7-membered chelate Sm-IV.

t-BuLi then

OH

PMBO

1. BzCl, pyr.

2. DDQ

I

Ph

PMBO

Ph

27

OHC

28

29

(58%, d.r. 50:50)

less conformationally rigid

H

OBz

HO

CH₃

SmI₂

H₂O

Ph

Sm

Ph

H

HO

Comparing results for lactate substrate 19 and Roche es-

ter-derived compound 12 demonstrates that the location of

the hydroxyl group (i.e., linker length) can impact both the

yield and selectivity for this reaction. To further investigate

this effect, we synthesized and examined the SmI₂(H₂O)_n

reductions of compounds 25 and 30, which contain hydrox-

30

31

HO

Sm-IV

CH₃

(71%, 2 steps)

(d.r. 63:37)

Scheme 6 Comparison of chelation size effects on SmI₂(H₂O)_nallylic

benzoate reductions. The reaction of 30 (B) gave lower diastereoselec-

tivity than compound 25 (A), presumably due to formation of a less

conformationally rigid 7-membered organosamarium chelate Sm-IV.

D

T. F. Stockdale et al.

Paper

Synthesis

organosamarium ring chelate Sm-IV would be less stable

and/or less conformationally rigid than 5- and 6-membered

chelate substrates.²⁸Indeed, the reaction of 30 with

SmI₂(H₂O)_ngave 31 with not only a lower diastereomeric

ratio (63:37), but was accompanied by large amounts of

what we have assigned as radical dimers.²²This result indi-

cates that favorable chelation not only improves d.r., but

also controls the product selectivity in these reactions.

Within the 5- and 6-membered chelate series we also

set out to evaluate the impact of stereodirecting group loca-

tion. To that end, several additional substrates 38a–c were

prepared (Scheme 7). Combined with compounds 12 and

25, we obtained data for SmI₂(H₂O)_nreductions for all per-

mutations of compounds proceeding through 5- or 6-mem-

bered chelates containing an , , or  methyl stereodirect-

ing group (Table 2). From these results certain trends

emerged. For instance, comparing results for compounds 12

and 38a (Table 2, entries 2 and 4) indicates that shifting the

stereocenter away from the allylic benzoate position results

in a slight loss of diastereoselectivity (75:25 for 12 vs 70:30

for 38a) with essentially no change in regioselectivity. This

could potentially be explained by the difference between

the primary alcohol in 12 and a secondary alcohol in 38a,

with a more sterically hindered alcohol resulting in a loss of

samarium chelation and therefore a less conformationally

restricted transition state. However, a similar shift of the

methyl group in the 6-membered chelate system (entries 3

and 5) resulted in a significant loss of diastereoselectivity

(78:22 for 25 vs 57:43 for 38b). This result cannot be ex-

plained by a change in the strength of the chelating group

as both 25 and 38b contain primary alcohols. Rather, it

seems that having the stereodirecting group closest to the

allylic benzoate position (and thus the resulting carbon-

bound samarium) is optimal for maximizing the diastereo-

selectivity of this reaction. Further evidence is provided

from the reduction of compound 38c (entry 6), with the

stereodirecting methyl group now further remote, and the

reaction giving low (and essentially identical to compound

38b) diastereoselectivity.

OH

AlMe₃, Cp₂ZrCl₂

1. BzCl, pyr.

38a

(86%)

Ph

OTBS

O

2. HF•pyr.

35

OTBS

(63%, d.r. 54:46)

32

OH

1. BzCl, pyr.

2. HF•pyr.

AlMe₃, Cp₂ZrCl₂

O

OTBS

OPMB

38b

(99%)

Ph

36

OTBS

(85%, d.r. 54:46)

33

OH

1. BzCl, pyr.

2. DDQ.

AlMe₃, Cp₂ZrCl₂

38c

(74%)

Ph

O

37

OPMB

(57%, d.r. 50:50)

34

Scheme 7 Synthesis of additional elimination substrates 37a–c con-

taining differing methyl stereocenter positioning

Table 2 Comparison of Chelation Size and Methyl Stereocenter Position on Regio- and Diastereoselectivity for SmI₂(H₂O)_nAllylic Benzoate Reductions^a

OBz

SmI₂

OH

+

( )_x( )_y

12, 25, 38a–c

( )_x( )_y

Ph

H₂O

see Table^a

15, 26, 39a–c

Entry

1

Starting material

Product

d.r.^b

r.r.^b

OBz

OH

α OH

86:14

98:2

Ph

21

13

19

OBz

α

2

3

4

5

6

75:25

78:22

70:30

57:43^c

56:44

98:2

100:0

88:12

94:6

Ph

OH

Ph

OH

12

OBz

OH

α

OH

Ph

26

25

OBz

β

OH

39a

39b

39c

38a

OBz

OH

38b

OBz

γ

83:17

Ph

38c

^aAll reactions were preformed using 105 equiv of H₂O and 7 equiv of SmI₂in degassed THF at r.t. under N₂.

^bDetermined by ¹H NMR and GC-FID analysis.

^cIdentical results were obtained when the reaction was performed under argon.

E

T. F. Stockdale et al.

Paper

Synthesis

Ozonolysis of the product mixtures obtained from the

reductions of compounds 25 and 38a produced oppositely

enantioenriched mixtures of aldehyde 15. From 25 we ob-

tained primarily S-(+)-15 whereas 38a gave primarily the

R-(–)-enantiomer.²³Both results are consistent with the

formation of chelated organosamarium transition state

structures Sm-III and Sm-IV, with the methyl group (Me)

assuming a preferred equatorial position (Scheme 8).

over a 5-membered ring chelate. Additionally, we also ob-

served an enhancement in d.r. by incorporation of i-Pr or

Bn-stereodirecting groups (Table 3, entries 2 and 5). Com-

bining these effects we thought it might therefore lead to

even further enhanced d.r. while still maintaining high

yield and regioselectivity. In order to test this hypothesis,

we synthesized the 6-membered chelate Bn-stereocenter

containing substrate 56 (Scheme 10). The synthesis began

by alkylation of oxazolidinone 52²⁹with benzyl bromide

giving 53 in 62% yield as a single diastereomer after chro-

matography on silica gel. DIBAL-H reduction of 53 gave al-

dehyde 54 to which was then added the lithium anion gen-

erated from vinyl iodide 27³⁰by lithium–halogen exchange.

This reaction produced secondary alcohol 55 as a 62:38

mixture of diastereomers in 93% yield. Benzoylation fol-

lowed by deprotection of the TBS ether using HF·pyr then

gave the final allylic benzoate ‘optimized substrate’ 56 in

81% over the two steps.

H

major diastereomer

CH₃

Ph

SmI₂

H₂O

O₃

25

(S)-(+)-15

(R)-(–)-15

Sm

Ph

H

then

Me₂S

HO

OH

26

CH₃

Sm-III

CH₃

H

major diastereomer

OH

O₃then

Me₂S

SmI₂

Sm

38a

Ph

H

Ph

H₂O

39a

CH₃

Sm-IV

Scheme 8 Determination of absolute stereochemistry for the major

diastereomers produced from the reactions of compounds 25 and 38a

and models Sm-III and Sm-IV to explain the outcome

OH

OPMB

OBz

R

OH

2

3

1

Ph

We also prepared a series of compounds 50a–e in order

to examine the effect of stereodirecting group identity in

these reactions (Scheme 9, Table 3). It was hypothesized

that larger groups might impart better diastereoselectivi-

ties based on, for instance, larger energy differences be-

tween axial and equatorial conformations. With the excep-

tion of substrates containing a hydroxyl (50e, entry 6) or

phenyl (50c, entry 4) stereodirecting group where elimina-

tion was an issue, all other substrates gave the desired

products in good yield and diastereoselectivity. Increasing

the size of the stereodirecting group appears to play a mod-

est role in the diastereoselectivity of the reaction. For in-

stance, a change in stereocenter identity from methyl (12,

entry 1) to isopropyl (50a, entry 2) resulted in an increase

in diastereoselectivity from 75:25 to 83:17; however, incor-

poration of an even larger tert-butyl group (50b, entry 3)

showed no further increase but rather a small drop in dias-

tereoselectivity (80:20). Reduction of the substrate 50c

containing a phenyl stereocenter (entry 4) gave the product

with a d.r. similar to that of a methyl stereodirecting group

(73:27 vs 75:25) but with a lower isolated yield (25%) due

to competing elimination to form the fully conjugated di-

ene. The use of a benzyl (Bn) stereocenter (50d, entry 5) re-

sulted in a d.r. similar to that obtained for an i-Pr group

(81:19). Regioselectivity for all reactions was high (from

93:7 to 100:0) suggestive of a dominant intramolecular

protonation pathway.

Ph

R

OPMB

45; R = i-Pr (75%, d.r. 91:9)

46; R = t-Bu (38%, d.r. 77:23)

47; R = Ph (59%, d.r. 98:2)

48; R = Bn (36%, d.r. 50:50)

50a; R = i-Pr (75%)

50b; R = t-Bu (42%)

50c; R = Ph (78%)

50d; R = Bn (82%)

OHC

R

40; R = i-Pr

41; R = t-Bu

42; R = Ph

43; R = Bn

OH

OBz

OH

4

Ph

O

OHC

O

44

5

O

OH

50e

49

O

(83%)

(50%, d.r. 74:26)

Scheme 9 Reagents and conditions: (1) AlMe₃, Cp₂ZrCl₂, then 40, 41,

42, 43, or 44; (2) BzCl, pyridine; (3) DDQ; (4) BzCl, pyridine; (5) pTSA,

MeOH.

Table 3 Stereodirecting Group Identity Effects on Regio- and Diaste-

reoselectivity for SmI₂(H₂O)_nAllylic Benzoate Reductions^a

OBz

OH

SmI₂

H₂O

+

Ph

13, 51a–e

Ph

R

12, 50a–e

see Table

Entry

R

d.r.^b

75:25

r.r.^b

Yield (%)^c

1

2

3

4

5

6

Me (12)

98:2

93:7

95:5

100:0

96:4

–

90

80

73

25

82

0

i-Pr (50a)

t-Bu (50b)

Ph (50c)

Bn (50d)

OH (50e)

83:17

80:20

73:27

81:19

–

Based on the results in Tables 2 and 3, we sought to de-

sign an optimized substrate for maximizing diastereoselec-

tivity in our SmI₂(H₂O)_nallylic benzoate reductions. For in-

stance, comparing results for compounds 12 and 25 (Table

2, entries 2 and 3) indicates a slightly higher d.r. from a 6-

membered ring chelated organosamarium intermediate

^aAll reductions were performed at r.t. using 7 equiv of SmI₂and 105 equiv

of H₂O.

^bDetermined by ¹H NMR analysis.

^cIsolated yield.

F

T. F. Stockdale et al.

Paper

Synthesis

trisubstituted alkene and flanked by a stereodirecting and

chelating group. The reaction can achieve high yields, regio-

selectivity, and diastereoselectivity (up to 90:10). Stereo-

directing- and chelating group location appear to have the

most significant impact on yield and selectivity in these re-

actions. Diastereoselectivity tends to increase with shorter

chain lengths between the allylic benzoate and the chelat-

ing group (e.g., 63:37 d.r. when separated by four carbons

vs 90:10 when separated by two). However, the highest dia-

stereoselectivity obtained (90:10) by having a chelating

hydroxyl immediately adjacent  to the allylic benzoate,

was accompanied by competing -elimination leading to

lower yields. Increasing the size of the stereodirecting

group also increased diastereoselectivity, although to a less-

er extent (e.g., 75:25 for methyl vs 80:20 for tert-butyl).

Combining the results from experiments investigating ster-

eodirecting and chelating group location along with stereo-

directing group identity effects, which led to the design and

synthesis of an ‘optimized substrate’ containing an -ben-

zyl stereodirecting group and a hydroxyl group that would

generate a 6-membered ring chelate organosamarium in-

termediate. Reduction of this compound with SmI₂(H₂O),

however, proceeded with low yield (32%) of the desired

product and modest diastereoselectivity (74:26). The low

yield was the result of moderate regioselectivity (69:31)

and the formation of side-products that we assume may in-

clude radical dimerization processes. Formation of larger-

ring-chelated organosamarium intermediates containing

sterically demanding groups might therefore not be favor-

able. Models have been proposed to account for these re-

sults based on ring-conformation considerations of a che-

lated organosamarium intermediate and a mechanism in-

volving intramolecular protonation by a samarium-bound

water.

O

OTBS

KHMDS, BnBr

N

O

N

O

–78 °C, 12 h

(62%)

Bn

52

53

Bn

I

O

H

DIBAL-H

t-BuLi

OTBS

+

Ph

–78 °C, 4 h

(56%)

Et₂O, –78 °C

(93%)

27

Bn

54

OBz

OH

1) BzCl, pyr.

OH

OTBS

Ph

2) HF•pyr.

Bn

56

Bn

(d.r. 62:38)

55

(81%, 2 steps)

Scheme 10 Synthesis of an optimized substrate 56 based on results

from Tables 2 and 3

Surprisingly upon reduction of 56 with SmI₂(H₂O)_n, the

expected product 57 was obtained in only 32% yield with a

d.r. of 74:26 and as a 69:31 mixture of regioisomers (r.r.,

Scheme 11). The low yield was due in part to a significant

level of side-product formation (e.g., radical dimers), which

1

were observed in the H NMR spectrum of the crude reac-

tion mixture. Other studies have shown that larger ions

such as samarium prefer smaller ring systems.³¹This may

explain the higher diastereo- and regioselectivity obtained

with the lactate derived substrate 20 (90:10) as it had the

smallest ring chelate size (nominal 4-membered³²). Addi-

tionally as the stereodirecting group becomes larger, steric

strain may be introduced into the rigid chelated organosa-

marium Sm-V. Formation of the 6-membered chelate Sm-V

from reduction of 56 may therefore not be as favorable,

leading to a greater percentage of side-products and lower

diastereo- and regioselectivity. Nonetheless, sufficient

amounts of 57 were obtained to determine its absolute con-

figuration. Ozonolysis of 57 followed by reduction with

NaBH₄gave (S)-(–)-58³³indicating the absolute stereo-

chemistry of the major diastereomer of 57 is (3S,6R). This is

consistent with a mechanism involving the 6-6 bicyclic or-

ganosamarium transition state structure Sm-V, with the

benzyl stereodirecting group occupying a preferred equato-

rial position, followed by intramolecular proton delivery

from a samarium bound water.

All reactions were carried out under N₂in flame-dried glassware, un-

less otherwise specified. The solvents used were dried by passing the

solvent through a column of activated Al₂O₃under N₂immediately

prior to use. SmI₂was prepared according to the method of Procter.³⁴

All other reagents were purchased and used as received, unless other-

wise mentioned. TLC analysis used 0.25 mm silica gel layer fluores-

cence UV₂₅₄plates. Flash chromatography: silica gel (230–400 mesh).

NMR: Spectra were recorded on a Varian Mercury 300 or Bruker 500

spectrometer in the solvents indicated; chemical shifts () are given

in ppm, coupling constants (J) in hertz (Hz). The solvent signals were

1) O₃

2) NaBH₄

OBz

SmI₂

H₂O

OH

(S)-(–)-58

Ph

(56%)

Bn

57

(d.r. = 74:26; r.r. = 69:31)

HO

56

HO

Bn

– Sm^IIIOBz

(32%)

H

O

H

O

H

SmI₂

used as references (CDCl₃: _c= 77.0; residual CHCl₃in CDCl₃: _H

=

H

Sm

H

7.26). MS (EI): Bruker MaXis Impact mass spectrometer. Spectral data

listed are for stereoisomeric mixtures unless specifically labelled to

the contrary.

HO

Bn

Ph

Bn

Sm-V

side reactions

CH₃

Scheme 11 Results from the SmI₂(H₂O)_nreduction of an ‘optimized’

substrate 56. The d.r. and regioselectivity (r.r.) obtained suggest that

the trends observed in Tables 2 and 3 may not be additive.

Zirconium-Catalyzed Carboalumination; General Procedure

To a Schlenk tube filled with DCM (0.3 M relative to alkyne) and

Cp₂ZrCl₂(0.1 equiv) at –20 °C was added AlMe₃(2.0 equiv) dropwise

resulting in a yellow solution, which was stirred for 10 min. Deionized

H₂O (1.0 equiv) was then added dropwise turning the solution a dark-

er shade of yellow, which was then stirred for another 10 min. The

In summary, samarium-mediated allylic benzoate re-

ductions can occur diastereoselectively when adjacent to a

G

T. F. Stockdale et al.

Paper

Synthesis

reaction was then warmed to r.t. for 10 min and then cooled to 0 °C.

Phenylacetylene (1.0 equiv) was added dropwise and the solution was

stirred for 40 min at 0 °C. The aldehyde (0.8 equiv) was then added

dropwise and the mixture was stirred for 1 h at 0 °C. The reaction was

quenched slowly with cold H₂O and then aq HCl, and extracted with

DCM (3 ×). The combined organic extracts were dried (MgSO₄) and

concentrated in vacuo.

chromatography on silica gel gave 8 (1.31 g, 85%) as a colorless oil (d.r.

= 70:30); R_f= 0.65 (1:1 hexanes:EtOAc).

IR (ATR): 3320, 3028, 2986, 2962, 2851, 1713, 1611, 1595, 1576, 1440,

1246, 1035, 699 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.43 (d, J = 7.1 Hz, 2 H), 7.34 (t, J = 7.3

Hz, 2 H), 7.29 (t, J = 8.7 Hz 3 H), 6.91 (d, J = 8.6 Hz, 2 H), 5.78 (dq, J =

8.9, 1.4 Hz, 1 H), 4.50 (d, J = 11.7 Hz, 1 H), 4.51 (m, 1 H), 4.47 (d, J =

11.7 Hz, 1 H), 3.83 (s, 3 H), 3.66 (dd, J = 9.3, 4.3 Hz, 1 H), 3.51 (dd, J =

9.3, 7.6 Hz, 1 H), 2.12 (d, J = 1.4 Hz, 3 H), 2.03 (qd, J = 7.4, 4.3 Hz, 1 H).

0.93 (d, J = 7.1 Hz, 3H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.27, 143.22, 137.42, 129.87,

129.50, 129.34, 128.15, 127.10, 125.88, 113.84, 74.49, 73.11, 73.10,

55.25, 39.34, 16.52, 13.45.

Benzoylation of Alcohols; General Procedure

Pyridine (2 equiv) was added to a Schlenk tube containing substrate

(1 equiv) in DCM (0.2 M relative to substrate). The mixture was then

cooled to 0 °C followed by the addition of benzoyl chloride (1.2 equiv).

The reaction was allowed to warm to r.t. for 15 h., before quenching

with aq NaHCO₃and extracting with DCM (3 ×). The combined organ-

ic extracts were dried (MgSO₄) and concentrated in vacuo.

HRMS (ES+): m/z [349.1780]⁺calcd for C₂₁H₂₆O₃Na⁺[M + Na]⁺; found:

349.1771.

DDQ Removal of a PMB; General Procedure

(2S,E)-1-[(4-Methoxybenzyl)oxy]-2-methyl-5-phenylhex-4-en-3-yl

Benzoate (9)

Substrate was added to a round-bottomed flask containing a 50:50

mixture of DCM:pH 7 buffer (0.1 M relative to substrate). The reaction

mixture was cooled to 0 °C and stirred vigorously at which time DDQ

(3 equiv) was added portionwise over 30 min. The reaction was

stirred vigorously for 1 h and then quenched with aq NaOH (1.0 M)

and extracted with DCM (3 ×). The combined organic extracts were

washed with brine (2 ×), dried (MgSO₄), and concentrated in vacuo.

Prepared according to the general benzoylation procedure using 8

(1.31 g, 4.00 mmol). Purification by flash chromatography on silica

gel gave 9 (1.72 g, quant.) as a colorless oil; R_f= 0.48 (4:1 hexanes:

EtOAc).

IR (ATR): 3063, 3032, 2999, 2962, 2934, 2917, 2851, 1786, 1713, 1611,

1599, 1584, 1450, 1246, 1035, 699 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 8.02 (dd, J = 7.0, 1.3 Hz, 2 H), 7.54 (dd,

J = 8.2, 7.6 Hz, 2 H), 7.42 (t, J = 8.0 Hz, 2 H), 7.38 (t, J = 7.0 Hz, 2 H), 7.31

(t, J = 7.2 Hz, 2 H), 7.25–7.21 (m, 2 H), 6.81 (d, J = 8.0 Hz, 2 H), 5.96 (dd,

J = 9.5, 6.8 Hz, 1 H), 5.77 (dq, J = 9.5, 1.4 Hz, 1 H), 4.45 (d, J = 11.7 Hz, 1

H), 4.40 (d, J = 11.7 Hz, 1 H), 3.77 (s, 3 H), 3.49 (t, J = 7.0 Hz, 1 H), 3.44

(dd, J = 6.0, 9.2 Hz, 1 H), 2.35 (hept, J = 6.9 Hz, 1 H), 2.27 (d, J = 1.3 Hz,

3 H), 1.11 (d, J = 7.0 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 165.73, 159.06, 143.00, 140.35,

134.54, 132.73, 130.59, 129.59, 129.24, 128.89, 128.29, 128.21,

127.40, 126.00, 124.06, 113.70, 73.37, 72.79, 71.60, 55.23, 38.33,

16.81, 13.09.

SmI₂(H₂O)_nReductions; General Procedure

To a dry Schlenk tube containing a solution of SmI₂in THF (0.1 M, 7

equiv) was added degassed nano-pure H₂O (105 equiv) turning the

solution to a deep red color. The solution was stirred for 5 min before

the substrate (1 equiv) was then added. After 30 min, the reaction was

quenched with aq NaHCO₃and extracted with EtOAc (3 ×). The com-

bined organic extracts were dried (MgSO₄), and concentrated in vac-

uo.

(E)-2,5-Diphenylhex-4-en-3-yl Benzoate (5)

Prepared according to the general benzoylation procedure using (E)-

2,5-diphenylhex-4-en-3-ol³⁵(0.5 g, 1.98 mmol). Purification by flash

chromatography on silica gel gave 5 (0.64 g, 90%) as a colorless oil (d.r.

= 80:20); R_f= 0.52 (4:1 hexanes:EtOAc).

HRMS (ES+): m/z [453.2042]⁺calcd for C₂₈H₃₀O₄Na⁺[M + Na]⁺; found:

453.2039.

IR (ATR): 3059, 3028, 2970, 1712, 1601, 1584, 1494, 1450, 1377, 1265,

1-Methoxy-4-({[(2R,E)-2-methyl-5-phenylhex-3-en-1-

yl]oxy}methyl)benzene (10)

998, 864, 710, 696 cm^–1

.

To a dry Schlenk flask containing a solution of SmI₂in THF (0.1 M,

16.1 mL) at 0 °C was added DMPU (0.445 mL, 1.61 mmol) resulting in

a dark purple solution, which was stirred for 1 h. Compound 9 (0.100

g, 0.23 mmol) was then added and the solution was stirred for 1 h.

The reaction was then quenched with aq NH₄Cl (20 mL) and extracted

with EtOAc (3 × 20 mL). The combined organic extracts were dried

(MgSO₄), and concentrated in vacuo. Purification by flash chromatog-

raphy on silica gel gave 10 (0.051 g, 70%) as a colorless oil (d.r. =

60:40); R_f= 0.60 (10:1 hexanes:EtOAc).

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 8.08 (ddd, J = 8.2, 3.2, 1.9 Hz, 2 H), 7.57

(dd, J = 6.8, 1.3 Hz, 1 H), 7.46 (t, J = 7.8 Hz, 2 H), 7.44–7.33 (m, 2 H),

7.33–7.26 (m, 5 H), 7.26–7.20 (m, 3 H), 6.01 (dd, J = 9.4, 7.5 Hz, 1 H),

5.64 (dq, J = 9.3, 1.4 Hz, 1 H), 3.29 (dq, J = 7.1 Hz, 1 H), 2.01 (d, J = 1.4

Hz, 3 H), 1.47 (d, J = 7.0 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 165.97, 143.02, 142.29, 139.89,

132.94, 130.60, 129.68, 128.42, 128.41, 128.27, 128.19, 127.35,

126.79, 125.99, 124.75, 76.04, 44.62, 17.16, 16.72.

IR (ATR): 3080, 3057, 3025, 2957, 2926, 2850, 1948, 1877, 1804, 1730,

1611, 1511, 1452, 1360, 1245, 1087, 1035, 819, 757, 698 cm^–1

.

HRMS (ES+): m/z [379.1674]⁺calcd for C₂₅H₂₄O₂Na⁺[M + Na]⁺; found:

¹H NMR (CDCl₃, 500 MHz):  = 7.29 (t, J = 7.5 Hz, 4 H), 7.20 (dd, J =

11.1, 2.3 Hz, 4 H), 7.17 (t, J = 6.7 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 4 H), 6.86

(d, J = 8.6 Hz, 4 H), 5.63 (ddd, J = 15.5, 6.7, 1.3 Hz, 2 H), 5.39 (ddd, J =

15.5, 7.1, 1.4 Hz, 2 H), 4.42 (d, J = 6.53 Hz, 4 H), 3.79 (s, 3 H), 3.78 (s, 3

H), 3.43 (pent, J = 7.0 Hz, 2 H), 3.32 (dd, J = 9.2, 6.2 Hz, 1 H), 3.31 (dd,

J = 9.1, 6.3 Hz, 1 H), 3.24 (dd, J = 9.2, 6.2 Hz, 1 H), 3.23 (dd, J = 7.1, 4.0

Hz, 1 H), 2.48 (hept, J = 6.7 Hz, 2 H), 1.31 (d, J = 7.0 Hz, 3 H), 1.00 (d, J =

6.8 Hz, 3 H). 0.99 (d, J = 6.6 Hz, 3 H).

379.1640.

(2S,E)-1-[(4-Methoxybenzyl)oxy]-2-methyl-5-phenylhex-4-en-3-

ol (8)

Prepared according to the general Zr-catalyzed carboalumination

procedure using aldehyde 7¹⁷(1.0 g, 4.7 mmol). Purification by flash

H

T. F. Stockdale et al.

Paper

Synthesis

¹³C NMR (CDCl₃, 126 MHz):  = 159.04, 134.62, 131.63, 129.13,

129.08, 128.30, 128.10, 127.18, 125.89, 113.70, 75.14, 72.50, 55.23,

42.20, 36.76, 21.48, 17.12.

Polarimetry value for (S)-15 from 21: []_D+88.5 (c 0.4, CHCl₃) {Lit.²³

for (R)-15: []_D–88.6 (c 0.93, CHCl₃).

HRMS (ES+): m/z [333.1830]⁺calcd for C₂₁H₂₆O₂Na⁺[M + Na]⁺; found:

(2R,E)-2-[(4-Methoxybenzyl)oxy]-5-phenylhex-4-en-3-ol (17)

333.1836.

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using aldehyde 16²⁶(0.500 g, 2.6 mmol). Purification

by flash chromatography over silica gel gave 17 (0.688 g, 82%) as a

colorless oil (d.r. = 58:42); R_f(diastereomer_) = 0.30; R_f(diastereo-

mer_) = 0.20 (4:1 hexanes:EtOAc).

(2S,E)-1-Hydroxy-2-methyl-5-phenylhex-4-en-3-yl Benzoate (12)

Prepared according to the general procedure for removal of a PMB

group with DDQ using 9 (1.2 g, 2.78 mmol). Purification by flash

chromatography on silica gel gave 12 (0.6 g, 70%) as a colorless oil; R_f=

0.18 (4:1 hexanes:EtOAc).

IR (ATR): 3328, 3058, 3016, 2928, 1268, 1110, 932, 711 cm^–1

.

Diastereomer 

IR (ATR): 3420, 3060, 3032, 2964, 2922, 2880, 1714, 1450, 1268, 1110,

932, 711 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.40 (dd, J = 8.6, 1.5 Hz, 2 H), 7.33 (t, J =

7.1 Hz, 2 H), 7.30 (d, J = 8.7 Hz, 2 H), 7.27 (t, J = 7.3 Hz, 1 H), 6.90 (d, J =

8.7 Hz, 2 H), 5.70 (dq, J = 8.9, 1.4 Hz, 1 H), 4.66 (d, J = 11.3 Hz, 1 H),

4.43 (d, J = 11.3 Hz 1 H), 4.38 (dd, J = 8.9, 7.7 Hz, 1 H), 3.82 (s, 3 H),

3.50 (dq, J = 7.7, 6.2 Hz, 1 H), 2.13 (d, J = 1.4 Hz, 3 H), 1.20 (d, J = 6.2 Hz,

3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.32, 142.98, 139.81, 130.21,

129.48, 128.18, 127.30, 126.40, 125.88, 113.92, 78.64, 72.44, 70.91,

55.26, 16.90, 15.52.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 8.07 (dd, J = 8.3, 1.2 Hz, 2 H), 7.57 (t, J =

7.4 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.42 (dd, J = 7.2, 1.3 Hz, 2 H), 7.33

(t, J = 7.7 Hz, 2 H), 7.28 (t, J = 7.2 Hz, 1 H), 5.95 (dd, J = 9.4, 8.1 Hz, 1 H),

5.84 (dq, J = 9.4, 1.4 Hz, 1 H), 3.68 (qd, J = 11.3, 4.6 Hz, 2 H), 2.23 (d, J =

1.4 Hz, 3 H), 2.15 (m, 1 H), 1.10 (d, J = 7.0 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 166.48, 142.73, 140.69, 133.05,

130.20, 129.67, 128.38, 128.25, 127.54, 125.96, 124.33, 73.31, 64.09,

40.55, 16.88, 12.92.

HRMS (ES+): m/z [335.1623]⁺calcd for C₂₀H₂₄O₃Na⁺[M + Na]⁺; found:

335.1612.

HRMS (ES+): m/z [333.1467]⁺calcd for C₂₁H₂₆O₂Na⁺[M + Na]⁺; found:

333.1472.

Diastereomer 

¹H NMR (CDCl₃, 500 MHz):  = 7.40 (dd, J = 8.7, 1.4 Hz, 2 H), 7.32 (t, J =

7.19 Hz, 2 H), 7.29 (d, J = 8.6 Hz, 2 H), 7.27 (t, J = 7.5 Hz, 1 H), 6.89 (d,

J = 8.7 Hz, 2 H), 5.80 (dq, J = 8.4, 1.3 Hz, 1 H), 4.62 (dd, J = 8.4, 3.6 Hz, 1

H), 4.62 (d, J = 11.7 Hz, 1 H), 4.50 (d, J = 11.7 Hz, 1 H), 3.81 (s, 3 H),

3.66 (qd, J = 6.4, 3.5 Hz, 1 H), 2.08 (d, J = 1.4 Hz, 3 H), 1.20 (d, J = 6.3 Hz,

3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.26, 143.03, 138.24, 130.57,

129.53, 129.31, 128.23, 127.26, 126.55, 125.89, 113.88, 77.19, 70.92,

70.62, 55.31, 16.56, 14.42.

(2R,5R,E)-2-Methyl-5-phenylhex-3-en-1-ol (13)

Prepared according to the general procedure for SmI₂(H₂O)_nreduc-

tions using compound 12 (0.025 g, 0.08 mmol). Purification by flash

chromatography on silica gel gave 15 (0.0135 g, 90%) as a pale yellow

oil; R_f= 0.31 (4:1 hexanes:EtOAc).

IR (ATR): 3360, 3083, 3061, 3025, 2961, 2925, 2871, 1950, 1876, 1803,

1716, 1601, 1492, 1415, 1373, 1272, 1029, 971, 760, 698 cm^–1

.

HRMS (ES+): m/z [335.1623]⁺calcd for C₂₀H₂₄O₃Na⁺[M + Na]⁺; found:

335.1612.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.38 (t, J = 4.7 Hz, 1 H), 7.30 (t, J = 6.9

Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 5.74 (ddd, J = 15.5, 6.8, 1.1 Hz, 1 H),

5.33 (ddd, J = 15.5, 7.9, 1.4 Hz, 1 H), 3.47 (m, 2 H), 3.38 (dd, J =10.6, 8.1

Hz, 1H), 2.36 (hept, J = 7.0 Hz, 1 H), 1.36 (d, J = 7.0 Hz, 3 H), 1.01 (d, J =

6.9 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 146.04, 136.89, 131.00, 128.43,

127.07, 126.06, 67.35, 42.27, 39.66, 21.48, 16.60.

(2R,E)-2-Hydroxy-5-phenylhex-4-en-3-yl Benzoate (19)

Prepared according to the general benzoylation procedure using 17

(0.371 g, 1.18 mmol). The general procedure for DDQ removal of the

PMB was then performed on the crude benzoylation product mixture

obtained. Purification by flash chromatography on silica gel gave 19

(0.281 g, 80% over two steps) as a colorless oil; R_f= 0.24 (4:1 hexanes:

EtOAc).

HRMS (ES+): m/z [190.1358]⁺calcd for C₁₃H₁₈O⁺[M]⁺; found:

190.1358.

IR (ATR): 3450, 3062, 3031, 2976, 2929, 1712, 1600, 1583, 1450, 1266,

1110, 1025, 963, 909, 709 cm^–1

.

(S)-2-Phenylpropanal (15)

To a round-bottomed flask open to air containing 13, 21, 26, or 39a in

DCM (0.1 M relative to substrate) at –78 °C, O₃was bubbled into the

solution until the reaction mixture turned to an electric blue color.

The reaction was left at this temperature without stirring for 5 min

and then N₂was bubbled though the reaction until the solution be-

came colorless. The reaction was quenched with Me₂S (5 equiv),

warmed to r.t., and stirred for 1 h. The reaction mixture was washed

with brine (15 mL) and extracted with DCM (3 × 15mL). The com-

bined organic extracts were dried (MgSO₄) and concentrated in vac-

uo. Aldehyde 15 was then isolated by flash chromatography on silica

gel; R_f= 0.63 (4:1 hexanes:EtOAc). NMR spectra for 15 matched with

that previously reported.²³

Diastereomer 

¹H NMR (CDCl₃, 500 MHz):  = 8.07 (dd, J = 8.3, 1.2 Hz, 2 H), 7.57 (t, J =

7.3 Hz, 1 H), 7.45 (t, J = 8.1 Hz, 2 H), 7.41 (dd, J = 8.4, 1.5 Hz, 2 H), 7.32

(t, J = 7.1 Hz, 2 H), 7.27 (t, J = 7.3 Hz, 1 H), 5.77 (m, 2 H), 4.10 (pent, J =

6.3 Hz, 1 H), 2.29 (d, J = 1.2 Hz, 3 H), 1.30 (d, J = 6.4 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 166.01, 142.54, 141.90, 133.09,

130.16, 129.66, 128.41, 128.27, 127.68, 125.96, 122.37, 69.74, 18.81,

17.07.

Diastereomer 

¹H NMR (CDCl₃, 500 MHz):  = 8.07 (dd, J = 8.3, 1.2 Hz, 2 H), 7.57 (t, J =

7.3 Hz, 1 H), 7.45 (t, J = 8.1 Hz, 2 H), 7.43 (dd, J = 8.4, 1.3 Hz, 1 H), 7.33

I

T. F. Stockdale et al.

Paper

Synthesis

(t, J = 7.1 Hz, 2 H), 7.28 (t, J = 7.3 Hz, 1 H), 5.91 (dq, J = 9.3, 1.3 Hz, 1 H),

5.85 (dd, J = 9.3, 4.0 Hz, 1 H), 4.15 (qd, J = 6.5, 4.1 Hz, 1 H), 2.25 (d, J =

1.3 Hz, 3 H), 1.31 (d, J = 6.4 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 165.94, 142.47, 142.03, 133.06,

130.15, 129.64, 128.39, 128.25, 127.66, 125.95, 122.37, 121.60, 76.73,

75.88, 69.59, 18.19, 16.90.

¹³C NMR (CDCl₃, 126 MHz):  = 166.05, 165.96, 144.48, 144.07,

132.97, 132.95, 130.44, 130.42, 129.64, 129.63, 128.37, 119.36,

118.42, 76.80, 75.83, 69.74, 69.54, 39.50, 39.46, 29.86, 29.80, 22.32,

22.30, 18.73, 18.12, 17.20, 17.09, 13.94.

HRMS (ES+): m/z [319.1310]⁺calcd for C₁₉H₂₀O₃Na⁺[M + Na]⁺; found:

319.1314.

HRMS (ES+): m/z [319.1310]⁺calcd for C₁₉H₂₀O₃Na⁺[M + Na]⁺; found:

319.1314.

(2R,5R,E)-5-Phenylhex-3-en-2-ol (21)

To a dry Schlenk tube containing a solution of SmI₂in THF (0.1 M, 7.0

mL, 7 equiv) was added degassed nano-pure H₂O (2.5 mL, 1400 equiv)

turning the solution to a deep red color. The solution was stirred for 5

min before compound 19 (0.030 g, 0.10 mmol) was then added. After

30 min, the reaction was quenched with aq NaHCO₃(15 mL) and ex-

tracted with EtOAc (3 × 15 mL). The combined organic extracts were

dried (MgSO₄), and concentrated in vacuo. Purification by flash chro-

matography on silica gel gave 21 (0.011 g, 60%) as a colorless oil (d.r. =

84:16); R_f= 0.30 (4:1 hexanes:EtOAc).

(2R,E)-2-[(4-Methoxybenzyl)oxy]-5-methylnon-4-en-3-ol (18)

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using 1-hexyne (0.373 mL, 3.25 mmol) and aldehyde

16²⁶(0.500 g, 2.6 mmol). Purification by flash chromatography on sil-

ica gel gave 18 (0.441 g, 58%) as a colorless oil (d.r. = 56:44); R_f(diaste-

reomer_) = 0.38; R_f(diastereomer_) = 0.34 (4:1 hexanes:EtOAc).

IR (ATR): 3420, 2980, 2928, 1614, 1570, 1265, 1110, 932, 886, 711 cm^–1

.

IR (ATR): 3462, 3062, 2956, 2929, 2871, 1714, 1600, 1578, 1450, 1315,

Diastereomer 

1266, 1111, 1068, 962, 709 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.29 (d, J = 8.3 Hz, 2 H), 6.91 (d, J = 8.7

Hz, 2 H), 5.13 (dq, J = 9.0, 1.3 Hz, 1 H), 4.64 (d, J = 11.4 Hz, 1 H), 4.42 (d,

J = 11.3 Hz, 1 H), 4.21 (dd, J = 9.0, 8.0 Hz, 1 H), 3.82 (s, 3 H), 3.39 (dq,

J = 8.0, 6.2 Hz, 1 H), 2.04 (t, J = 7.7 Hz, 2 H), 1.71 (d, J = 1.4 Hz, 3 H),

1.42 (m, 2 H), 1.31 (hept, J = 7.3 Hz, 2 H), 1.13 (d, J = 6.2 Hz, 3 H), 0.92

(t, J = 7.3 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.22, 141.64, 130.31, 129.37,

123.08, 113.84, 78.91, 72.09, 70.80, 55.20, 39.38, 29.79, 22.29, 16.97,

15.36, 13.92.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.30 (t, J = 7.6 Hz, 2 H), 7.22–7.18 (m, 3

H), 5.82 (ddd, J = 15.4, 6.7, 1.1 Hz, 1 H), 5.56 (ddd, J = 15.5, 6.6, 1.4 Hz,

1 H), 4.30 (pent, J = 6.4 Hz, 1 H), 3.46 (pent, J = 7.0, 6.4 Hz, 1 H), 1.36

(d, J = 7.0 Hz, 3 H), 1.28 (d, J = 6.4 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 145.56, 135.41, 132.87, 128.44,

127.16, 126.16, 68.87, 41.83, 23.42, 21.17.

HRMS (ES+): m/z [159.1174]⁺calcd for C₁₂H₁₅[M – OH]⁺; found:

159.1175.

Diastereomer 

¹H NMR (CDCl₃, 500 MHz):  = 7.27 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7

Hz, 2 H), 5.20 (dq, J = 8.5, 1.3 Hz, 1 H), 4.57 (d, J = 11.5 Hz, 1 H), 4.47 (d,

J = 11.1 Hz, 1 H), 4.46 (dd, J = 8.3, 3.9 Hz, 1 H), 3.81 (s, 3 H), 3.55 (qd,

J = 6.4, 3.4 Hz, 1 H), 2.01 (t, J = 7.0 Hz, 2 H), 1.64 (d, J = 1.4 Hz, 3 H),

1.39 (pent, J = 7.5 Hz, 2 H), 1.29 (m, 2 H), 1.12 (d, J = 6.4 Hz, 3 H), 0.89

(t, J = 7.3 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.17, 140.08, 130.70, 129.20,

122.97, 113.81, 77.32, 70.50, 70.37, 55.28, 39.39, 29.91, 22.34, 16.66,

14.17, 13.97.

(2R,5S,E)-5-Methylnon-3-en-2-ol (22)

To a dry Schlenk tube containing a solution of SmI₂in THF (0.1 M, 7.7

mL, 7 equiv) was added degassed nano-pure H₂O (2.75 mL, 1400

equiv) turning the solution to a deep red color. The solution was

stirred for 5 min before compound 20 (0.030 g, 0.11 mmol) was add-

ed. After 30 min, the reaction was quenched with aq NaHCO₃(15 mL)

and extracted with EtOAc (3 × 15 mL). The combined organic extracts

were dried (MgSO₄), and concentrated in vacuo. Purification by flash

chromatography on silica gel gave 22 (0.010 g, 60%) as a colorless oil

(d.r. = 90:10); R_f= 0.38 (4:1 hexanes:EtOAc).

HRMS (ES+): m/z [315.1936]⁺calcd for C₁₈H₂₈O₃Na⁺[M + Na]⁺; found:

315.1944.

IR (ATR): 3347, 2958, 2925, 2871, 2857, 1606, 1457, 1371, 1258, 1150,

1123, 1060, 969, 730 cm^–1

.

(2R,E)-2-Hydroxy-5-methylnon-4-en-3-yl Benzoate (20)

Prepared according to the general benzoylation procedure using 18

(0.431 g, 1.3 mmol). The general procedure for DDQ removal of the

PMB was then performed on the crude benzoylation product mixture

obtained. Purification by flash chromatography on silica gel gave 20

(0.344 g, 89%) as a colorless oil; R_f= 0.32 (4:1 hexanes:EtOAc).

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 5.54 (dd, J = 15.4, 6.9 Hz, 1 H), 5.48 (dd,

J = 15.4, 6.0 Hz, 1 H), 4.28 (pent, J = 6.3 Hz, 1 H), 2.11 (pent, J = 6.6 Hz,

1 H), 1.29 (m, 6 H), 1.28 (d, J = 6.3 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H),

0.90 (t, J = 7.0 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 136.99, 132.24, 69.03, 36.56, 36.14,

29.48, 23.49, 22.79, 20.40, 14.08.

IR (ATR): 3462, 3062, 2956, 2929, 2871, 1714, 1600, 1578, 1450, 1315,

1266, 1111, 1068, 962, 709 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 8.05 (dd, J = 8.5, 1.3 Hz, 4 H), 7.55 (t, J =

7.4 Hz, 2 H), 7.44 (t, J = 7.7 Hz, 4 H), 5.66 (dd, J = 9.2, 4.4 Hz, 1 H), 5.57

(dd, J = 9.5, 7.2 Hz, 1 H), 5.32 (dq, J = 9.2, 1.3 Hz, 1 H), 5.20 (dq, J = 9.5,

1.3 Hz, 1 H), 4.03 (qd, J = 6.3, 4.2 Hz, 1 H), 3.97 (pent, J = 6.6 Hz, 1 H),

2.06 (t, J = 7.6 Hz, 2 H), 2.04 (t, J = 7.3 Hz, 2 H), 1.84 (d, J = 1.4 Hz, 3 H),

1.81 (d, J = 1.4 Hz, 3 H), 1.40 (m, 4 H), 1.29 (pent, J = 7.4 Hz, 4 H), 1.24

(d, J = 6.5 Hz, 3 H), 1.22 (d, J = 6.5 Hz, 3 H), 0.89 (t, J = 7.3 Hz, 3 H), 0.88

(t, J = 7.3 Hz, 3 H).

HRMS (ES+): m/z [139.1487]⁺calcd for C₁₀H₁₉[M – OH]⁺; found:

139.1482.

(5S,E)-7-[(4-Methoxybenzyl)oxy]-5-methyl-2-phenylhept-2-en-4-

ol (24)

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using (2S)-4-{[(1,1-dimethylethyl)dimethylsilyl]oxy}

-2-methylbutanal (23;³⁶0.29 g, 1.3 mmol). Purification by flash

J

T. F. Stockdale et al.

Paper

Synthesis

chromatography on silica gel gave 24 (0.288 g, 65%) as a colorless oil

(d.r. = 60:40); R_f= 0.65 (1:1 hexanes:EtOAc).

by flash chromatography over silica gel gave 29 (0.097 g, 58%) as a

colorless oil (d.r. = ~50:50); R_f= 0.64 (1:1 hexanes:EtOAc).

IR (ATR): 3396, 3102, 3080, 3056, 3028, 2931, 2863, 1611, 1585, 1511,

1493, 1444, 1364, 1301, 1245, 1081, 1032, 909, 820, 757, 731, 696

IR (ATR): 3412, 3080, 3056, 3031, 2931, 2856, 1611, 1585, 1511, 1493,

1444, 1362, 1301, 1245, 1172, 1092, 1032, 821, 758, 735, 696 cm^–1

.

cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.40 (dt, J = 8.4, 1.5 Hz, 4 H), 7.33 (tt, J =

8.3, 1.0 Hz, 4 H), 7.27 (tt, J = 4.1, 1.3 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 4 H),

6.87 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 5.80 (dq, J = 8.9, 1.5 Hz,

1 H), 5.78 (dq, J = 9.0, 1.4 Hz, 1 H), 4.44 (s, 2 H), 4.43 (s, 2 H), 4.38 (dd,

J = 8.9, 5.7 Hz, 1 H), 4.35 (dd, J = 8.9, 6.5 Hz, 1 H), 3.80 (s, 3 H), 3.79 (s,

3 H), 3.48–3.42 (m, 4 H), 2.10 (d, J = 1.4 Hz, 3 H), 2.09 (d, J = 1.4 Hz, 3

H), 1.80–1.59 (m 10 H), 1.00 (d, J = 6.7 Hz, 3 H), 0.93 (d, J = 6.7 Hz, 3

H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.09, 143.17, 138.01, 137.65,

130.68, 129.38, 129.24, 129.22, 128.98, 128.24, 127.25, 127.22,

125.86, 113.75, 72.67, 72.65, 72.57, 72.55, 70.38, 70.32, 55.27, 39.51,

39.44, 28.96, 28.93, 27.53, 27.21, 16.59, 16.50, 14.97, 14.95.

¹H NMR (CDCl₃, 500 MHz):  = 7.42–7.38 (m, 4 H), 7.32 (t, 7.32, J = 7.3

Hz, 4 H), 7.27 (dd, J = 5.6, 2.1 Hz, 2 H), 7.26 (dd, J = 7.0, 2.0 Hz, 2 H),

7.25 (tt, J = 6.3, 1.3 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz,

2 H), 5.82 (dq, J = 8.7, 1.4 Hz, 1 H), 5.77 (dq, J = 8.9, 1.4 Hz, 1 H), 4.47 (s,

2 H), 4.47 (d, J = 11.5 Hz, 1 H), 4.44 (d, J = 11.5 Hz, 1 H), 4.43 (dd, J =

9.1, 4.5 Hz, 1 H), 4.30 (dd, J = 8.8, 6.9 Hz, 1 H), 3.81 (s, 3 H), 3.80 (s, 3

H), 3.63–3.56 (m, 2 H), 3.54–3.49 (m, 2 H), 2.63 (br, OH), 2.40 (br, OH),

2.08 (d, J = 1.4 Hz, 3 H), 2.07 (d, J = 1.4 Hz, 3 H), 1.92–1.81 (m, 4 H),

1.64 (sept, J = 6.7 Hz, 1 H), 1.50 (sept, J = 6.6 Hz, 1 H), 0.98 (d, J = 6.5

Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.23, 143.31, 137.56, 137.26,

130.20, 129.55, 129.39, 129.37, 129.19, 128.20, 127.14, 125.90,

113.84, 113.83, 72.78, 72.77 72.71, 72.20, 68.36, 68.03, 55.28, 37.80,

37.56, 32.96, 32.77, 16.61, 16.51, 16.00, 15.21.

HRMS (ES+): m/z [377.2093]⁺calcd for C₂₃H₃₀O₃Na⁺[M + Na]⁺; found:

377.2094.

HRMS (ES+): m/z [363.1936]⁺calcd for C₂₂H₂₈O₃Na⁺[M + Na]⁺; found:

363.1939.

(5S,E)-8-Hydroxy-5-methyl-2-phenyloct-2-en-4-yl Benzoate (30)

Prepared according to the general benzoylation procedure using 29

(0.097 g, 0.27 mmol). The general procedure for DDQ removal of the

PMB was then performed on the crude benzoylation product mixture

obtained. Purification by flash chromatography on silica gel gave 30

(0.065 g, 71%) as a colorless oil; R_f= 0.13 (4:1 hexanes:EtOAc).

(5S,E)-7-Hydroxy-5-methyl-2-phenylhept-2-en-4-yl Benzoate (25)

Prepared according to the general benzoylation procedure using 24

(0.288 g, 0.85 mmol). The general procedure for DDQ removal of the

PMB was then performed on the crude benzoylation product mixture

obtained. Purification by flash chromatography on silica gel gave 25

(0.238 g, 86% over two steps) as a colorless oil; R_f= 0.15 (4:1 hexanes:

EtOAc).

IR (ATR): 3400, 3059, 3031, 2931, 2876, 1712, 1600, 1583, 1493, 1450,

1380, 1314, 1266, 1175, 1107, 1068, 1025, 908, 731 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 8.06 (dt, J = 8.4, 1.0 Hz, 4 H), 7.55 (tq,

J = 6.9, 1.3 Hz, 2 H), 7.44 (t, J = 7.6 Hz, 4 H), 7.40 (dt, J = 8.5, 1.5 Hz, 4

H), 7.31 (tt, J = 7.38, 1.0 Hz, 4 H), 7.26 (tq, J = 7.2, 1.3 Hz, 2 H), 5.82 (m,

4 H), 3.67 (tt, J = 6.5, 2.0 Hz, 4 H), 2.24 (d, J = 1.0 Hz, 3 H), 2.23 (s, 3 H),

2.04 (m, 1 H), 1.97 (m, 1 H), 1.77–1.54 (m, 8 H), 1.12 (d, J = 6.9 Hz, 3

H), 1.09 (d, J = 6.8 Hz, 3 H).

IR (ATR): 3047, 3059, 3031, 2967, 2931, 2877 1713, 1600, 1583, 1450,

1314, 1266, 1175, 1108, 1068, 909, 848, 731 cm^–1

.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.40 (dt, J = 8.4, 1.5 Hz, 4 H), 7.33 (tt, J =

8.3, 1.0 Hz, 4 H), 7.27 (tt, J = 4.1, 1.3 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 4 H),

6.87 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 5.80 (dq, J = 8.9, 1.5 Hz,

1 H), 5.78 (dq, J = 9.0, 1.4 Hz, 1 H), 4.44 (s, 2 H), 4.43 (s, 2 H), 4.38 (dd,

J = 8.9, 5.7 Hz, 1 H), 4.35 (dd, J = 8.9, 6.5 Hz, 1 H), 3.80 (s, 3 H), 3.79 (s,

3 H), 3.48–3.42 (m, 4 H), 2.10 (d, J = 1.4 Hz, 3 H), 2.09 (d, J = 1.4 Hz, 3

H), 1.80–1.59 (m 10 H), 1.00 (d, J = 6.7 Hz, 3 H), 0.93 (d, J = 6.7 Hz, 3

H).

¹³C NMR (CDCl₃, 126 MHz):  = 166.33, 166.30, 143.26, 143.23,

140.64, 140.32, 133.21, 130.95, 129.96, 129.95, 128.71, 128.59,

127.82, 127.80, 126.33, 124.91, 124.56, 75.94, 75.78, 61.33, 61.24,

35.77, 35.74, 35.20, 34.97, 17.27, 17.18, 15.78, 15.61.

¹³C NMR (CDCl₃, 126 MHz):  = 165.97, 165.94, 142.93, 142.89,

140.14, 139.65, 132.79, 130.65, 129.57, 128.31, 128.20, 127.40,

127.38, 125.95, 125.94, 124.83, 124.27, 75.53, 75.45, 63.07, 63.06,

38.05, 37.56, 30.45, 30.17, 28.60, 28.56, 16.87, 16.78, 15.30, 15.05.

HRMS (ES+): m/z [361.1780]⁺calcd for C₂₂H₂₆O₃Na⁺[M + Na]⁺; found:

361.1780.

(6S,E)-6-[(tert-Butyldimethylsilyl)oxy]-2-phenylhept-2-en-4-ol

(35)

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using (S)-3-[(tert-butyldimethylsilyl)oxy]butanal

(32;³⁸0.231 g, 1.15 mmol). Purification by flash chromatography on

silica gel gave 35 (0.234 g, 63%) as a colorless oil (d.r. = 54:46); R_f=

0.52 (4:1 hexanes:EtOAc).

HRMS (ES+): m/z [347.1623]⁺calcd for C₂₁H₂₄O₃Na⁺[M + Na]⁺; found:

347.1622.

IR (ATR): 3413, 3081, 3057, 3027, 2955, 2928, 2855, 1612, 1512, 1494,

(5S,E)-8-[(4-Methoxybenzyl)oxy]-5-methyl-2-phenyloct-2-en-4-ol

(29)

1462, 1374, 1248, 1143, 1077, 1001, 834, 807, 774, 756, 731, 695 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.41 (d, J = 7.1 Hz, 4 H), 7.31 (t, J = 7.4

Hz, 4 H), 7.24 (t, J = 7.2 Hz 2 H), 5.83 (dq, J = 8.6, 1.3 Hz, 1 H), 5.79 (dq,

J = 8.2, 1.4 Hz, 2 H), 4.90 (dt, J = 8.9, 3.1 Hz, 1 H), 4.72 (dt, J = 8.9, 3.1

Hz, 1 H), 4.23 (pentd, J = 6.2, 3.6 Hz, 1 H), 4.16 (dtd, J = 12.2, 6.1, 3.8

Hz, 1 H), 3.35 (br, OH), 3.13 (br, OH), 2.10 (d, J = 1.4 Hz, 3 H), 2.10 (d,

J = 1.4 Hz, 3 H), 1.83 (ddd, J = 9.1, 7.0, 3.4 Hz, 1 H), 1.80 (ddd, J = 9.2,

5.2, 1.6 Hz, 1 H), 1.63 (dddd, J = 14.3, 6.91, 3.8, 3.2 Hz, 1 H), 1.60

(dddd, J = 14.3, 8.7, 6.2, 2.6 Hz, 1 H), 1.28 (d, J = 6.3 Hz, 3 H), 1.23 (d, J =

6.1 Hz, 3 H), 0.93 (s, 18 H), 0.14 (d, J = 9.1 Hz, 6 H), 0.12 (d, J = 8.1 Hz, 6

H).

To a Schlenk flask containing Et₂O (5.2 mL) and t-BuLi (1.7 M, 0.917

mL, 1.56 mL) at –78 °C was added vinyl iodide 27³⁰(0.190 g, 0.78

mmol) dropwise. The solution was stirred for 10 min at –78 °C before

adding

(2S)-5-[(4-methoxyphenyl)methoxy]-2-methylpentanal

(28;³⁷0.123g, 0.520 mmol) dropwise, and the reaction mixture was

stirred for 1 h at –78 °C. The reaction was quenched with aq NH₄Cl

(30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic

extracts were dried (MgSO₄), and concentrated in vacuo. Purification

K

T. F. Stockdale et al.

Paper

Synthesis

¹³C NMR (CDCl₃, 126 MHz):  = 143.24, 143.21, 136.54, 135.96,

131.13, 130.86, 128.33, 127.25, 127.22, 125.99, 125.94, 69.63, 68.69,

67.20, 66.06, 46.31, 45.03, 25.97, 24.71, 23.29, 18.11, 18.07, 16.52,

16.28, –3.66, –4.26, –4.65, –4.83.

66.58, 43.19, 42.31, 33.90, 32.30, 25.85, 18.26, 18.23, 17.76, 17.38,

16.14, –5.46, –5.51, –5.53.

HRMS (ES+): m/z [357.2226]⁺calcd for C₂₀H₃₄O₂SiNa⁺[M + Na]⁺;

found: 357.2222.

HRMS (ES+): m/z [343.2069]⁺calcd for C₁₉H₃₂O₂SiNa⁺[M + Na]⁺;

found: 343.2065.

(E)-7-Hydroxy-6-methyl-2-phenylhept-2-en-4-yl Benzoate (38b)

Prepared according to the general benzoylation procedure using 36

(0.250g, 0.747 mmol). The crude product mixture was placed into a

Teflon reaction vessel containing THF (7.4 mL), cooled to 0 °C, and

treated with HF·pyr (70% HF, 0.400 mL, 12.064 mmol) and left to sit

for 18 h at 4 °C without stirring. The reaction was quenched with aq

NaHCO₃and extracted with EtOAc (3 × 10 mL). The combined organic

extracts were dried (MgSO₄), and concentrated in vacuo. Purification

by flash chromatography on silica gel gave 38b (0.240 g, 99% over two

steps) as a colorless oil; R_f= 0.18 (4:1 hexanes:EtOAc).

(6S,E)-6-Hydroxy-2-phenylhept-2-en-4-yl Benzoate (38a)

Prepared according to the general benzoylation procedure using 35

(0.234 g, 0.729 mmol). The crude product mixture was placed into a

Teflon reaction vessel containing THF (7.3 mL), cooled to 0 °C, and

treated with HF·pyr (70% HF, 0.400 mL, 12.064 mmol) and left to sit

for 18 h at 4 °C without stirring. The reaction was quenched with aq

NaHCO₃and extracted with EtOAc (3 × 10 mL). The combined organic

extracts were dried (MgSO₄), and concentrated in vacuo. Purification

by flash chromatography over silica gel gave 38a (0.194 g, 86% over

two steps) as a colorless oil; R_f(diastereomer_) = 0.24; R_f(diastereo-

mer_) = 0.18 (4:1 hexanes:EtOAc).

IR (ATR): 3429, 3065, 3032, 2962, 2919, 2877, 1712, 1600, 1583, 1450,

1314, 1267, 1108, 1069, 1025, 931, 711 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 8.05 (d, 8.0 Hz, 4 H), 7.55 (tt, 7.5, 1.1

Hz, 2 H), 7.44 (t, J = 7.8 Hz, 4 H), 7.41 (dd, J = 7.6, 1.8 Hz, 4 H), 7.32 (t,

7.2 Hz, 4 H), 7.26 (tt, J = 7.3, 1.2 Hz, 2 H), 6.06 (dt, J = 6.8, 9.1 Hz, 1 H),

6.04 (dt, J = 8.7, 5.3 Hz, 1 H), 5.81 (dq, J = 9.0, 1.3 Hz, 1 H), 5.78 (dq, J =

9.2, 1.3 Hz, 1 H), 3.57 (dd, J = 5.6, 1.8 Hz, 4 H), 2.24 (d, J = 1.3 Hz, 3 H),

2.23 (d, J = 1.3 Hz, 3 H), 1.98 (m, 2 H), 1.94–1.78 (m, 4 H), 1.05 (d, J =

6.7 Hz, 3 H), 1.04 (d, J = 6.4 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 166.15, 166.10, 142.72, 142.69,

139.52, 138.98, 132.89, 132.87, 130.60, 130.53, 129.63, 129.62,

128.35, 128.26, 127.50, 127.47, 126.59, 126.35, 125.97, 125.96, 71.00,

70.58, 68.16, 68.02, 38.67, 32.47, 32.37, 17.17, 16.83, 16.71, 16.65.

IR (ATR): 3428, 3060, 3032, 1713, 1600, 1584, 1450, 1266, 1108, 1068,

1025, 934, 847, 731 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 8.06 (t, J = 9.2 Hz, 4 H), 7.58 (tt, J = 7.4,

1.2 Hz, 1 H), 7.55 (tt, J = 7.4, 1.2 Hz, 1 H), 7.45 (t, J = 8.0 Hz, 4 H), 7.41

(d, J = 7.51 Hz, 4 H), 7.33 (t, J = 7.2 Hz, 2 H), 7.32 (t, J = 7.5 Hz, 2 H),

7.27 (tt, J = 5.88, 1.3 Hz, 2 H), 6.19 (dd, J = 8.8, 3.5 Hz, 1 H), 6.10 (dt, J =

6.90 Hz, 1 H), 5.90 (dq, J = 8.7, 1.4 Hz, 1 H), 5.80 (dq, J = 9.2, 1.2 Hz, 1

H), 3.97 (qd, J = 6.2, 1.4 Hz, 1 H), 3.86 (qd, J = 6.2, 2.6 Hz, 1 H), 2.26 (d,

J = 1.2 Hz, 3 H), 2.19 (t, J = 1.2 Hz, 3 H), 2.13 (ddd, J =14.0, 8.3, 6.6 Hz, 1

H), 1.99 (ddd, J = 13.3, 10.4, 2.6 Hz, 1 H), 1.88 (ddd, J = 11.5, 7.3, 4.5 Hz,

1 H), 1.80 (ddd, J = 13.7, 10.0, 3.3 Hz, 1 H), 1.29 (d, J = 6.2 Hz, 3 H), 1.24

(d, J = 6.2 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 167.10, 165.91, 142.66, 142.52,

139.76, 139.26, 133.20, 132.91, 130.52, 130.02, 129.79, 129.60,

128.42, 128.36, 128.30, 128.26, 127.59, 127.53, 125.96, 125.93,

125.87, 125.76, 70.75, 69.88, 65.46, 63.63, 45.08, 44.24, 24.14, 23.08,

16.66.

HRMS (ES+): m/z [347.1623]⁺calcd for C₂₁H₂₄O₃Na⁺[M + Na]⁺; found:

347.1619.

(E)-7-[(4-Methoxybenzyl)oxy]-2-phenyloct-2-en-4-ol (37)

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using 4-[(4-methoxybenzyl)oxy]pentanal (34;⁴⁰

0.300 g, 1.3 mmol). Purification by flash chromatography on silica gel

gave 37 (0.254 g, 57%) as a colorless oil (d.r. = 50:50); R_f= 0.61 (4:1

hexanes:EtOAc).

HRMS (ES+): m/z [333.1467]⁺calcd for C₂₀H₂₂O₃Na⁺[M + Na]⁺; found:

333.1483.

IR (ATR): 3395, 3080, 3056, 3030, 2930, 2861, 1611, 1585, 1512, 1493,

(E)-7-[(tert-Butyldimethylsilyl)oxy]-6-methyl-2-phenylhept-2-en-

4-ol (36)

1443, 1374, 1337, 1301, 1172, 1032, 911, 821, 757, 733, 696 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.41 (d, J = 7.8 Hz, 4 H), 7.33 (t, J = 7.3

Hz, 4 H), 7.28 (dd, J = 8.8, 1.5 Hz, 4 H), 7.26 (tt, J = 6.5, 1.2 Hz, 2 H),

6.88 (dd, J = 8.6, 2.0 Hz, 4 H), 5.78 (dq, J = 5.4, 1.4 Hz, 1 H), 5.77 (dq J =

5.4, 1.4 Hz, 1 H), 4.54 (d, J = 11.5 Hz, 4 H), 4.40 (dd, J = 11.3, 2.4 Hz, 2

H), 3.80 (s, 6 H), 3.57 (hex, 5.9 Hz, 2 H), 2.08 (d, J = 1.3 Hz, 3 H), 2.08

(d, J = 1.3 Hz, 3 H), 1.81–1.56 (m, 8 H), 1.22 (d, J = 6.2 Hz, 6 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.06, 142.97, 142.95, 136.80,

136.72, 130.86, 130.84, 129.26, 129.24, 128.18, 127.15, 125.78,

113.74, 74.44, 74.43, 70.02, 69.98, 68.96, 68.89, 55.22, 33.67, 33.58,

32.56, 32.51, 19.49, 19.47, 16.29, 16.27.

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using 4-[(tert-butyldimethylsilyl)oxy]-3-methylbu-

tanal (33;³⁹0.500 g, 2.31 mmol). Purification by flash chromatogra-

phy on silica gel gave 36 (0.658 g, 85%) as a colorless oil (d.r. = 54:46);

R_f= 0.51 (4:1 hexanes:EtOAc).

IR (ATR): 3347, 3082, 3058, 3028, 2954, 2927, 2855, 1598, 1495, 1471,

1462, 1387, 1360, 1250, 1153, 1089, 1028, 1005, 833, 774, 755, 694

cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.43 (d, J = 7.8 Hz, 4 H), 7.33 (t, J = 7.4

Hz, 4 H), 7.26 (tq, J = 7.4, 1.3 Hz, 2 H), 5.83 (tq, J = 8.5, 1.4 Hz, 2 H), 4.72

(td, J = 7.3, 6.2 Hz, 1 H), 4.64 (td, J = 8.8, 3.8 Hz, 1 H), 3.60 (dd, J = 10,

4.7 Hz, 1 H), 3.58 (dd, 5.2, 9.9 Hz, 1 H), 3.52 (dd, J = 9.9, 6.7 Hz, 1 H),

3.48 (dd, J = 10.0, 7.4 Hz, 1 H), 3.25 (br, OH), 2.95 (br, OH), 2.12 (d, J =

1.4 Hz, 6 H), 1.89 (octet, J = 6.6 Hz, 2 H), 1.72 (ddd, J = 14.3, 9.2, 7.1 Hz,

1 H), 1.66 (ddd, J = 7.2, 6.1, 3.6 Hz, 2 H), 1.49 (ddd, J = 14.1, 5.9, 3.7 Hz,

1 H), 0.98 (d, J = 6.8 Hz, 6 H), 0.95 (s, 9 H), 0.95 (s, 9 H), 0.12 (d, J = 2.7

Hz, 6 H), 0.11 (d, J = 2.2 Hz, 6 H).

HRMS (ES+): m/z [377.2093]⁺calcd for C₂₃H₃₀O₃Na⁺[M + Na]⁺; found:

377.2094.

(E)-7-Hydroxy-2-phenyloct-2-en-4-yl Benzoate (38c)

Prepared according to the general benzoylation procedure using 37

(0.288 g, 0.845 mmol). The general procedure for DDQ removal of the

PMB was then performed on the crude benzoylation product mixture

obtained. Purification by flash chromatography on silica gel gave 38c

(0.180 g, 74% over two steps) as a colorless oil; R_f= 0.15 (4:1 hexanes:

EtOAc).

¹³C NMR (CDCl₃, 126 MHz):  = 143.07, 143.05, 136.02, 135.69,

131.58, 131.19, 128.08, 126.97, 126.94, 125.74, 69.01, 68.39, 67.71,

L

T. F. Stockdale et al.

Paper

Synthesis

IR (ATR): 3411, 3059, 3031, 2967, 2927, 2866, 1712, 1601, 1583, 1493,

1450, 1376, 1314, 1267, 1175, 1109, 1069, 1025, 710 cm^–1

(dtd, J = 6.7, 5.0, 4.1 Hz, 1 H), 1.09 (d, J = 6.9 Hz, 3 H), 1.04 (d, J = 6.9 Hz,

3 H).

.

¹H NMR (CDCl₃, 500 MHz):  = 8.06 (dd, J = 8.5, 1.3 Hz, 4 H), 7.55 (tt,

J = 7.4, 1.2 Hz, 2 H), 7.44 (t, J = 8.0 Hz, 4 H), 7.41 (dd, J = 7.6, 1.6 Hz, 4

H), 7.32 (t, J = 7.8 Hz, 4 H), 7.26 (tt, J = 7.2, 1.4 Hz, 2 H), 5.95 (dt, J = 6.9,

6.7 Hz, 1 H), 5.94 (dt, J = 6.9, 6.7 Hz, 1 H), 5.81 (dq, J = 9.0, 1.3 Hz, 2 H),

3.88 (hex, J = 6.5 Hz, 2 H), 2.22 (d, J = 1.4 Hz, 3 H), 2.21 (d, J = 1.3 Hz, 3

H), 2.05 (qt, J = 6.94, 5.49 Hz, 1 H), 1.95 (dt, J = 6.8, 6.4 Hz, 1 H), 1.93

(dt, J = 6.7, 6.5 Hz, 1 H), 1.83 (qt, J = 6.0, 3.9 Hz, 1 H), 1.63–1.54 (m, 4

H), 1.23 (d, J = 6.3 Hz, 6 H).

¹³C NMR (CDCl₃, 126 MHz):  = 166.08, 166.03, 142.72, 142.70,

139.39, 139.32, 133.63, 132.86, 132.85, 130.60, 130.17, 129.62,

128.48, 128.33, 128.25, 127.49, 127.47, 126.16, 126.14, 125.96, 72.28,

72.15, 67.93, 67.88, 34.70, 34.56, 31.42, 31.31, 23.70, 23.67, 16.71.

¹³C NMR (CDCl₃, 126 MHz):  = 166.06, 142.67, 139.70, 133.07,

130.29, 129.57, 128.48, 128.26, 127.53, 125.95, 125.46, 73.06, 60.79,

51.30, 27.00, 21.42, 19.50, 16.69.

HRMS (ES+): m/z [361.1780]⁺calcd for C₂₂H₂₆O₃Na⁺[M + Na]⁺; found:

361.1758.

(E)-5-{[(4-Methoxybenzyl)oxy]methyl}-6,6-dimethyl-2-phenyl-

hept-2-en-4-ol (46)

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using 2-{[(4-methoxybenzyl)oxy]methyl}-3,3-di-

methylbutanal (41;⁴²0.387 g, 1.54 mmol). Purification by flash chro-

matography on silica gel gave 46 (0.175 g, 38%) as a colorless oil (d.r. =

77:23); R_f= 0.43 (4:1 hexanes:EtOAc).

HRMS (ES+): m/z [361.1780]⁺calcd for C₂₂H₂₆O₃Na⁺[M + Na]⁺; found:

361.1780.

IR (ATR): 3445, 3080, 3056, 3027, 2954, 2868, 1611, 1586, 1512, 1493,

1464, 1443, 1363, 1301, 1246, 1206, 1075, 1034, 986, 819, 757, 696

cm^–1

.

(E)-5-{[(4-Methoxybenzyl)oxy]methyl}-6-methyl-2-phenylhept-2-

en-4-ol (45)

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using 2-{[(4-methoxybenzyl)oxy]methyl}-3-methyl-

butanal (40;⁴¹0.346 g, 1.46 mmol). Purification by flash chromatogra-

phy on silica gel gave 45 (0.392 g, 75%) as a colorless oil (d.r. = 91:9);

R_f= 0.34 (4:1 hexanes:EtOAc).

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.33 (dd, J = 8.3, 1.7 Hz, 2 H), 7.30 (t, J =

7.8 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 2 H), 7.24 (tt, J = 6.0, 1.6 Hz, 1 H), 6.87

(d, J = 8.6 Hz, 2 H), 5.98 (dq, J = 8.3, 1.4 Hz, 1 H), 4.89 (td, J = 8.3, 2.5 Hz,

1 H), 4.46 (d, J = 11.4 Hz, 1 H), 4.42 (d, J = 11.4 Hz, 1 H), 3.83 (dd, J =

4.1, 1.5 Hz, 2 H), 3.80 (s, 3 H), 3.32 (d, J = 8.3 Hz, 1 H), 2.05 (d, J = 1.3

Hz, 3 H), 1.42 (td, J = 4.2, 2.6 Hz, 1 H), 1.10 (s, 9 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.26, 143.33, 133.83, 132.89,

129.81, 129.45, 128.10, 126.85, 125.81, 113.81, 73.19, 69.71, 68.84,

55.23, 52.86, 33.39, 29.26, 15.95.

IR (ATR): 3456, 3080, 3055, 3028, 2956, 2870, 1611, 1585, 1512, 1443,

1418, 1366, 1301, 1246, 1173, 1079, 1032, 987, 909, 819, 757, 732,

696 cm^–1

.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.37 (dd, J = 8.6, 1.4 Hz, 2 H), 7.32 (t, J =

7.2 Hz, 2 H), 7.27 (dd, J = 8.7, 2.1 Hz, 2 H), 7.25 (tt, J = 7.3, 2.2 Hz, 1 H),

6.89 (dt, J = 8.7, 2.1 Hz, 2 H), 5.81 (dq, J = 8.5, 1.3 Hz, 1 H), 4.72 (dt, J =

8.6, 5.8 Hz, 1 H), 4.49 (d, J = 11.5 Hz, 1 H), 4.45 (d, J = 11.5 Hz, 1 H),

3.81 (s, 3 H), 3.79 (dd, J = 9.5, 3.0 Hz, 1 H), 3.68 (dd, J = 9.5, 5.7 Hz, 1

H), 2.06 (d, J = 1.3 Hz, 3 H), 2.04 (hex, J = 6.8 Hz, 1 H), 1.47 (qd, J = 6.0,

3.0 Hz, 1 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 6.9 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.34, 143.20, 135.77, 131.06,

129.69, 129.47, 128.13, 126.98, 125.82, 113.86, 73.24, 70.87, 69.43,

55.25, 50.01, 26.35, 21.52, 19.25, 16.12.

HRMS (ES+): m/z [391.2249]⁺calcd for C₂₄H₃₂O₃Na⁺[M + Na]⁺; found:

391.2257.

(E)-5-(Hydroxymethyl)-6,6-dimethyl-2-phenylhept-2-en-4-ylBen-

zoate (50b)

Prepared according to the general benzoylation procedure using 46

(0.144 g, 0.391 mmol). The general procedure for DDQ removal of the

PMB was then performed on the crude benzoylation product mixture

obtained. Purification by flash chromatography on silica gel gave 50b

(0.060 g, 42% over two steps) as a colorless oil; R_f= 0.35 (4:1 hexanes:

EtOAc).

HRMS (ES+): m/z [377.2093]⁺calcd for C₂₃H₃₀O₃Na⁺[M + Na]⁺; found:

377.2076.

IR (ATR): 3459, 3059, 3030, 2958, 2873, 1713, 1600, 1583, 1493, 1476,

1450, 1367, 1269, 1175, 1110, 1040, 910, 711 cm^–1

.

(E)-5-(Hydroxymethyl)-6-methyl-2-phenylhept-2-en-4-yl Benzo-

ate (50a)

Major Diastereomer

Prepared according to the general benzoylation procedure using 45

(0.392 g, 1.11 mmol). The general procedure for DDQ removal of the

PMB was then performed on the crude benzoylation product mixture

obtained. Purification by flash chromatography on silica gel gave 50a

(0.281 g, 75% over two steps) as a colorless oil; R_f= 0.50 (4:1 hexanes:

EtOAc).

¹H NMR (CDCl₃, 500 MHz):  = 8.02 (dd, J = 8.3, 1.3 Hz, 2 H), 7.56 (tt,

J = 7.0, 1.3 Hz, 1 H), 7.45 (tt, J = 7.7, 1.5 Hz, 2 H), 7.40 (dd, J = 7.0, 1.5

Hz, 2 H), 7.30 (tt, J = 7.1, 1.5 Hz, 2 H), 7.24 (tt, J = 7.1, 1.3 Hz, 1 H), 6.33

(dd, J = 9.0, 2.2 Hz, 1 H), 6.06 (dq, J = 9.0, 1.4 Hz, 1 H), 4.18 (dd, J = 11.7,

6.1 Hz, 1 H), 4.08 (dd, J = 11.7, 4.1 Hz, 1 H), 2.27 (d, J = 1.4 Hz, 3 H),

1.72 (ddd, J = 6.2, 4.1, 2.2 Hz, 1 H), 1.08 (s, 9 H).

IR (ATR): 3459, 3083, 3060, 3080, 2958, 2930, 2884, 1712, 1600, 1583,

¹³C NMR (CDCl₃, 126 MHz):  = 165.60, 142.74, 137.24, 132.99,

130.44, 129.47, 128.47, 128.19, 127.33, 127.10, 125.93, 72.25, 60.94,

55.52, 33.20, 28.82, 16.51.

HRMS (ES+): m/z [375.1936]⁺calcd for C₂₃H₂₈O₃Na⁺[M + Na]⁺; found:

375.1937.

1493, 1450, 1387, 1314, 1266, 1176, 1109, 1069, 1025, 920, 710 cm^–1

.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 8.03 (dd, J = 8.5, 1.3 Hz, 2 H), 7.57 (tt,

J = 7.4, 1.3 Hz, 1 H), 7.45 (tt, J = 7.9, 1.5 Hz, 2 H), 7.41 (dd, J = 7.4, 1.5

Hz, 2 H), 7.32 (t, J = 7.1 Hz, 2 H), 7.27 (tt, J = 7.3, 1.3 Hz, 1 H), 6.19 (dd,

J = 9.3, 6.7 Hz, 1 H), 5.90 (dq, J = 9.3, 1.3 Hz, 1 H), 3.90 (dd, J = 4.5, 3.7

Hz, 2 H), 2.26 (d, J = 1.4 Hz, 3 H), 2.00 (hexd, J = 6.9, 5.1 Hz, 1 H), 1.79

(E)-1-[(4-Methoxybenzyl)oxy]-2,5-diphenylhex-4-en-3-ol (47)

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using 3-[(4-methoxybenzyl)oxy]-2-phenylpropanal

M

T. F. Stockdale et al.

Paper

Synthesis

(42;⁴³(0.113 g, 0.42 mmol). Purification by flash chromatography on

silica gel gave 47 (0.097 g, 59%) as a colorless oil (d.r. = 98:2); R_f= 0.19

(4:1 hexanes:EtOAc).

(dq, J = 8.9, 1.4 Hz, 1 H), 5.87 (dq, J = 8.6, 1.3 Hz, 1 H), 4.75 (dd, J = 8.9,

3.8 Hz, 1 H), 4.60 (t, J = 7.3 Hz, 1 H), 4.46 (d, J = 11.5 Hz, 1 H), 4.44 (d,

J = 11.5 Hz, 1 H), 4.41 (d, J = 11.5 Hz, 2 H), 4.36 (d, J = 11.5 Hz, 1 H),

3.81 (s, 6 H), 3.71 (dd, J = 9.4, 3.5 Hz, 1 H), 3.51 (dd, J = 9.2, 6.0 Hz, 1

H), 3.48 (dd, J = 9.7, 4.2 Hz, 1 H), 3.46 (dd, J = 9.4, 5.2 Hz, 1 H), 3.26 (br,

OH), 3.10 (br, OH), 2.93 (dd, J = 13.7, 5.8 Hz, 1 H), 2.83 (dd, J = 13.7, 5.3

Hz, 1 H), 2.70 (dd, J = 9.5, 3.5 Hz, 1 H), 2.67 (dd, J = 9.5, 3.9 Hz, 1 H),

2.27 (dtt, J = 9.7, 5.8, 4.1 Hz, 1 H), 2.08 (d, J = 1.4 Hz, 3 H), 2.05 (m, 1

H), 2.02 (d, J = 1.3 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.30, 159.28, 143.17, 143.09,

140.33, 140.29, 137.46, 136.81, 130.04, 129.86, 129.81, 129.47,

129.43, 129.10, 129.07, 128.36, 128.32, 128.30, 128.18, 128.15,

127.15, 127.10, 125.97, 125.92, 125.86, 125.83, 113.82, 73.12, 73.10,

71.23, 71.22, 70.48, 70.12, 55.23, 46.39, 46.36, 34.74, 32.93, 16.48,

16.27.

IR (ATR): 3419, 3082, 3059, 3028, 2999, 2915, 2858, 1611, 1585, 1512,

1493, 1452, 1362, 1301, 1246, 1173, 1076, 1030, 908, 819, 730, 697

cm^–1

.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.35–7.27 (m, 2 H), 7.26 (d, J = 8.7 Hz, 2

H), 7.24–7.15 (m, 8 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.60 (dq, J = 8.9, 1.4 Hz,

1 H), 4.88 (td, J = 8.6, 3.0 Hz, 1 H), 4.55 (d, J = 11.6 Hz, 1 H), 4.51 (d, J =

11.6 Hz, 1 H), 3.99 (dd, J = 9.4, 8.3 Hz, 1 H), 3.88 (dd, J = 9.4, 4.7 Hz, 1

H), 3.81 (s, 3 H), 3.45 (d, J = 3.1 Hz, OH), 3.14 (td, J = 8.1, 4.6 Hz, 1 H),

1.82 (d, J = 1.4 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 159.35, 143.37, 139.37, 137.61,

129.65, 129.44, 129.06, 128.65, 128.30, 128.03, 126.97, 126.89,

125.90, 113.89, 73.23, 73.11, 72.64, 55.28, 51.75, 16.40.

HRMS (ES+): m/z [425.2093]⁺calcd for C₂₇H₃₀O₃Na⁺[M + Na]⁺; found:

425.2112.

HRMS (ES+): m/z [411.1936]⁺calcd for C₂₆H₂₈O₃Na⁺[M + Na]⁺; found:

411.1938.

(E)-2-Benzyl-1-hydroxy-5-phenylhex-4-en-3-yl Benzoate (50d)

Prepared according to the general benzoylation procedure using 48

(0.102 g, 0.254 mmol). The general procedure for DDQ removal of the

PMB was then performed on the crude benzoylation product mixture

obtained. Purification by flash chromatography on silica gel gave 50d

(0.081 g, 82% over two steps) as a colorless oil; R_f= 0.32 (4:1 hexanes:

EtOAc).

(E)-1-Hydroxy-2,5-diphenylhex-4-en-3-yl Benzoate (50c)

Prepared according to the general benzoylation procedure was using

47 (0.097 g, 0.249 mmol). The general procedure for DDQ removal of

the PMB was then performed on the crude benzoylation product mix-

ture obtained. Purification by flash chromatography on silica gel gave

50c (0.065 g, 78% over two steps) as a colorless oil; R_f= 0.37 (4:1

hexanes:EtOAc).

IR (ATR): 3467, 3104, 3083, 3061, 3026, 2926, 1713, 1600, 1583, 1493,

1450, 1373, 1314, 1266, 1175, 1111, 1068, 1025, 909, 758, 733, 711

cm^–1

.

IR (ATR): 3460, 3083, 3060, 3029, 2923, 1713, 1600, 1583, 1511, 1493,

¹H NMR (CDCl₃, 500 MHz):  = 8.08 (dd, J = 8.2, 1.2 Hz, 2 H), 8.06 (dd,

J = 8.1, 1.2 Hz, 2 H), 7.59 (m, 1 H), 7.58 (m, 1 H), 7.47 (t, J = 7.6 Hz, 4 H),

7.44–7.40 (m, 2 H), 7.40–7.32 (m, 6 H), 7.32–7.27 (m, 6 H), 7.26–7.19

(m, 6 H), 6.23 (dd, J = 8.9, 4.8 Hz, 1 H), 6.10 (dd, J = 9.4, 7.6 Hz, 1 H),

5.97 (dq, J = 6.1, 1.3 Hz, 1 H), 5.95 (dq, J = 6.5, 1.3 Hz, 1 H), 3.71 (dd, J =

11.7, 3.5 Hz, 1 H), 3.66 (dd, J = 11.5, 4.6 Hz, 1 H), 3.61–3.55 (m, 2 H),

3.05 (dd, J = 14.0, 4.9 Hz, 1 H), 2.87 (dd, J = 13.6, 5.1 Hz, 1 H), 2.80 (dd,

J = 13.6, 9.8 Hz, 1 H), 2.69 (dd, J = 14.0, 9.5 Hz, 1 H), 2.39 (ddq, J = 9.6,

7.2, 4.8 Hz, 1 H), 2.24 (m, 1 H), 2.23 (d, J = 1.4 Hz, 3 H), 2.21 (d, J = 1.4

Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 166.46, 166.45, 142.66, 142.64,

140.96, 139.94, 139.92, 139.91, 133.14, 133.11, 130.16, 130.10,

129.71, 129.69, 129.19, 128.97, 128.53, 128.49, 128.43, 128.29,

128.26, 127.63, 127.54, 126.18, 125.99, 125.93, 124.47, 124.32, 72.31,

61.79, 60.15, 48.05, 47.63, 33.17, 33.04, 16.86, 16.72.

1450, 1315, 1266, 1109, 1068, 1025, 907, 710 cm^–1

.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.99 (dd, J = 8.3, 1.2 Hz, 2 H), 7.49 (tt,

7.0, 1.2 Hz, 1 H), 7.37 (tt, J = 7.9, 1.5 Hz, 2 H), 7.25 (dd, J = 4.2, 1.0 Hz, 4

H), 7.19–7.16 (m, 2 H), 7.16–7.12 (m, 2 H), 7.12–7.09 (m, 2 H), 6.17 (t,

J = 9.0 Hz, 1 H), 5.56 (dq, J = 9.5, 1.4 Hz, 1 H), 3.97 (d, J = 5.9 Hz, 2 H),

3.26 (dt, J = 8.7, 5.9 Hz, 1 H), 1.93 (d, J = 1.3 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 166.14, 142.79, 140.52, 138.28,

133.10, 130.13, 129.68, 129.05, 128.56, 128.41, 128.10, 127.38,

127.36, 125.92, 124.40, 72.63, 63.45, 53.03, 16.76.

HRMS (ES+): m/z [395.1623]⁺calcd for C₂₅H₂₄O₃Na⁺[M + Na]⁺; found:

395.1610.

(E)-2-Benzyl-1-[(4-methoxybenzyl)oxy]-5-phenylhex-4-en-3-ol

(48)

(E)-1-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-phenylbut-2-en-1-ol

(49)

To a Schlenk flask containing Et₂O (3.5 mL) and t-BuLi (1.7 M, 0.905

mL, 1.54 mL) at –78 °C was added vinyl iodide 27³⁰(0.171 g, 0.702

mmol) dropwise. The solution was stirred for 10 min at –78 °C and 2-

benzyl-3-[(4-methoxybenzyl)oxy]propanal (43;⁴³0.100 g, 0.351

mmol) was then added dropwise. The reaction mixture was stirred

for 1 h at –78 °C before being brought to r.t. for 30 min. The reaction

was quenched with aq NH₄Cl (30 mL) and extracted with EtOAc (3 ×

20 mL). The combined organic extracts were dried (MgSO₄) and con-

centrated in vacuo. Purification by flash chromatography over silica

gel gave 48 (0.051 g, 36%) as a colorless oil (d.r. = 50:50); R_f= 0.22 (4:1

hexanes:EtOAc).

Prepared according to the general procedure for Zr-catalyzed car-

boaluminations using (R)-2,2-dimethyl-1,3-dioxolane-4-carboxalde-

hyde (44; 0.500 g, 3.8 mmol). Purification by flash chromatography

on silica gel gave 49 (0.586 g, 50%) as a colorless oil (d.r. = 74:26); R_f=

0.66 (1:1 hexanes:EtOAc).

IR (ATR): 3450, 3060, 3034, 2990, 2800, 1665, 1601, 1585, 1501, 1453,

1386, 1310, 1076, 853 cm^–1

.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.40 (dd, J = 8.1, 1.5 Hz, 2 H), 7.33 (t, J =

7.1 Hz, 2 H), 7.27 (tt, J = 7.2, 1.4 Hz, 1 H), 5.68 (dq, J = 8.5, 1.4 Hz, 1 H),

4.73 (ddd, J = 8.4, 3.9, 2.9 Hz, 1 H), 4.20 (td, J = 6.9, 4.1 Hz, 1 H), 4.02

(dd, J = 8.2, 6.6 Hz, 1 H), 4.00 (dd, 8.4, 8.2 Hz, 1 H), 2.14 (d, J = 1.3 Hz, 3

H), 1.48 (s, 3 H), 1.39 (s, 3 H).

IR (ATR): 3430, 3034, 2917, 2849, 1600, 1594, 1493, 1454, 1442, 1382,

1333, 1244, 1201, 1160, 1033, 968, 919, 836, 745, 687 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.40–7.33 (m, 6 H), 7.33–7.28 (m, 4 H),

7.28–7.24 (m, 8 H), 7.23–7.14 (m, 6 H), 6.89 (d, J = 8.7 Hz, 4 H), 5.89

N

T. F. Stockdale et al.

Paper

Synthesis

¹³C NMR (CDCl₃, 126 MHz):  = 142.57, 139.96, 128.29, 127.55,

125.93, 125.89, 125.05, 109.28, 78.14, 68.35, 64.70, 26.45, 25.22,

16.78.

HRMS (ES+): m/z [271.1310]⁺calcd for C₁₅H₂₀O₃Na⁺[M + Na]⁺; found:

271.1316.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.30 (t, J = 7.65 Hz, 2 H), 7.23–7.17 (m,

3 H), 5.78 (ddd, J = 15.3, 6.8, 0.6 Hz, 1 H), 5.36 (ddd, J = 15.3, 9.9, 1.4

Hz, 1 H), 3.74 (dd, J = 10.3, 3.8 Hz, 1 H), 3.53 (pent, J = 6.8 Hz, 1 H),

3.36 (t, J = 10.3 Hz, 1 H), 1.95 (td, J = 10.3, 4.0 Hz, 1 H), 1.38 (d, J = 7.0

Hz, 3 H), 0.91 (s, 9 H).

(2R,E)-1,2-Dihydroxy-5-phenylhex-4-en-3-yl Benzoate (50e)

¹³C NMR (CDCl₃, 126 MHz):  = 145.99, 140.50, 128.51, 127.52,

127.01, 126.12, 61.84, 56.49, 42.55, 32.07, 28.08, 21.54.

HRMS (ES+): m/z [255.1725]⁺calcd for C₁₆H₂₄ONa⁺[M + Na]⁺; found:

255.1725.

Prepared according to the general benzoylation procedure using 49

(0.45 g, 2.13 mmol). The crude product was then redissolved in MeOH

(8.5 mL) and pTSA (0.404 g, 2.128 mmol) was added. The reaction

mixture was stirred for 5 min before quenching with aq NaHCO₃(10

mL) and extracting with DCM (3 × 10 mL). The combined organic ex-

tracts were dried (MgSO₄), and concentrated in vacuo. Purification by

flash chromatography on silica gel gave 50e (0.223 g, 83%) as a color-

less oil; R_f= 0.25 (1:1 hexanes:EtOAc).

2,5-Diphenylhex-3-en-1-ol (51c)

Prepared according to the general procedure for SmI₂(H₂O)_nreduc-

tions using 50c (0.066 g, 0.176 mmol). Purification by flash chroma-

tography on silica gel gave 51c (0.012 g, 25%) as a colorless oil (d.r. =

73:27); R_f= 0.28 (4:1 hexanes:EtOAc).

IR (ATR): 3389, 3061, 3032, 2926, 2881, 1712, 1600, 1583, 1493, 1450,

1382, 1265, 1176, 1111, 1068, 1025, 907, 710 cm^–1

.

IR (ATR): 3427, 3026, 2924, 1601, 1492, 1451, 1271, 1031, 758 cm^–1

.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 8.08 (dd, J = 8.0, 1.4 Hz, 2 H), 7.59 (tt,

J = 7.4, 1.4 Hz, 1 H), 7.47 (t, J = 8.1 Hz, 2 H), 7.45 (dd, J = 8.5, 1.5 Hz, 2

H), 7.35 (t, J = 7.0 Hz, 2 H), 7.30 (tt, J = 7.15, 1.4 Hz, 1 H), 5.99 (dd, J =

9.3, 5.8 Hz, 1 H), 5.94 (dq, J = 9.1, 1.3 Hz, 1 H), 4.03 (td, J = 5.9, 3.2 Hz,

1 H), 3.85 (dd, J = 11.7, 3.3 Hz, 1 H), 3.76 (dd, J = 11.7, 6.1 Hz, 1 H), 2.26

(d, J = 1.3 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 166.22, 142.54, 142.26, 133.30,

129.75, 128.45, 128.29, 127.80, 125.97, 121.93, 73.59, 72.10, 62.78,

16.95.

¹H NMR (CDCl₃, 500 MHz):  = 7.34 (t, J = 7.6 Hz, 2 H), 7.30 (t, J = 7.6

Hz, 2 H), 7.26–7.17 (m, 6 H), 5.82 (ddd, J = 15.6, 6.7, 0.88 Hz, 1 H), 5.66

(ddd, J = 15.4, 8.0, 1.3 Hz, 1 H), 3.87 (m, 1 H), 3.77 (pent, J = 8.15 Hz, 2

H), 3.51 (q, J = 7.5 Hz, 1 H). 1.36 (d, J = 7.1 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 138.13, 128.73, 128.48, 127.90,

127.12, 126.83, 126.15, 66.51, 51.46, 42.38, 21.40.

HRMS (ES+): m/z [275.1412]⁺calcd for C₁₈H₂₀ONa⁺[M + Na]⁺; found:

275.1412.

HRMS (ES+): m/z [335.1259]⁺calcd for C₁₉H₂₀O₄Na⁺[M + Na]⁺; found:

335.1265.

2-Benzyl-5-phenylhex-3-en-1-ol (51d)

Prepared according to the general procedure for SmI₂(H₂O)_nreduc-

tions using 50d (0.050 g, 0.147 mmol). Purification by flash chroma-

tography on silica gel gave 51d (0.030 g, 82%) as a colorless oil (d.r. =

81:19); R_f= 0.37 (4:1 hexanes:EtOAc).

2-Isopropyl-5-phenylhex-3-en-1-ol (51a)

Prepared according to the general procedure for SmI₂(H₂O)_nreduc-

tions using 50a (0.050 g, 0.147 mmol). Purification by flash chroma-

tography on silica gel gave 51a (0.026 g, 80%) as a colorless oil (d.r. =

83:17); R_f= 0.37 (4:1 hexanes:EtOAc).

IR (ATR): 3352, 3056, 3026, 2964, 2925, 2869, 1600, 1580, 1493, 1452,

1424, 1303, 1208, 1108, 1031, 973, 840, 800, 700 cm^–1

.

IR (ATR): 3352, 3056, 2959, 2926, 2870, 1600, 1580, 1492, 1451, 1367,

Major Diastereomer

1303, 1208, 1108, 1031, 908, 732, 699 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.29 (t, J = 7.1 Hz, 2 H), 7.24 (t, J = 7.7

Hz, 2 H), 7.21 (tt, J = 6.2, 2.1 Hz, 1 H), 7.19–7.08 (m, 3 H), 7.03 (d, J =

7.3 Hz, 2 H), 5.64 (ddd, J = 15.5, 6.4, 0.8 Hz, 1 H), 5.31 (ddd, J = 15.4,

8.4, 1.4 Hz, 1 H), 3.61 (dd, J = 10.5, 4.9 Hz, 1 H), 3.48 (dd, J = 10.5, 7.5

Hz, 1 H), 3.42 (pent, J = 6.5 Hz, 1 H), 2.80 (dd, J = 13.1, 6.0 Hz, 1 H),

2.60 (dd, J = 13.2, 8.4 Hz, 1 H), 2.54 (dtd, J = 13.8, 7.8, 5.0 Hz, 1 H), 1.28

(d, J = 7.1 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 145.83, 139.81, 138.48, 129.25,

129.00, 128.36, 128.23, 127.09, 126.01, 125.92, 65.44, 47.45, 42.14,

37.88, 21.31.

Major Diastereomer

¹H NMR (CDCl₃, 500 MHz):  = 7.31 (t, J = 7.5 Hz, 2 H), 7.22 (dd, J = 6.6,

1.6 Hz, 2 H), 7.20 (tt, J = 6.7, 1.3 Hz, 1 H), 5.76 (ddd, J = 15.4, 6.7, 0.7

Hz, 1 H), 5.28 (ddd, J = 15.4, 9.5, 1.4 Hz, 1 H), 3.65 (dd, J = 10.5, 5.0 Hz,

1 H), 3.51 (pent, J = 6.9 Hz, 1 H), 3.41 (dd, J = 10.5, 9.0 Hz, 1 H), 2.00

(tdd, J = 9.6, 6.9, 5.3 Hz, 1 H), 1.67 (octet, J = 6.7 Hz, 1 H), 1.38 (d, J = 7.0

Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 146.01, 139.51, 128.45, 128.05,

127.04, 126.06, 64.15, 52.46, 42.47, 28.89, 21.54, 20.86, 19.65.

HRMS (ES+): m/z [241.1568]⁺calcd for C₁₅H₂₂ONa⁺[M + Na]⁺; found:

241.1558.

HRMS (ES+): m/z [289.1568]⁺calcd for C₁₉H₂₂ONa⁺[M + Na]⁺; found:

289.1563.

(S)-4-Benzyl-3-{(S)-2-benzyl-4-[(tert-butyldimethylsilyl)oxy]-

butanoyl}oxazolidin-2-one (53)

2-(tert-Butyl)-5-phenylhex-3-en-1-ol (51b)

Prepared according to the general procedure for SmI₂(H₂O)_nreduc-

tions using 50b (0.075 g, 0.212 mmol). Purification by flash chroma-

tography on silica gel gave 51b (0.027 g, 73%) as a colorless oil (d.r. =

80:20); R_f= 0.33 (4:1 hexanes:EtOAc).

To a Schlenk flask containing oxazolidinone 52²⁶(1.56 g, 4.14 mmol)

in THF (20.73 mL) at –78 °C was added KHMDS (1 M in THF, 9.94 mL,

9.94 mmol) dropwise. The reaction mixture was stirred at –78 °C for

1 h before freshly distilled benzyl bromide (1.22 mL, 9.94 mmol) was

added dropwise. The mixture was stirred for 12 h at –78 °C before

quenching with aq NH₄Cl (40 mL) and extracting with EtOAc (3 × 20

IR (ATR): 3436, 3055, 2963, 2873, 1599, 1597, 1512, 1441, 1365, 1255,

1108, 1032, 909, 732 cm^–1

.

O

T. F. Stockdale et al.

Paper

Synthesis

mL). The combined organic extracts were dried (MgSO₄), and concen-

trated in vacuo. Purification by flash chromatography on silica gel

gave 53 (1.01 g, 62%) as a colorless oil; R_f= 0.51 (4:1 hexanes:EtOAc).

¹H NMR (CDCl₃, 500 MHz):  = 7.42 (d, J = 7.5 Hz, 2 H), 7.40 (d J = 8.0

Hz, 2 H), 7.33 (t, J = 7.3 Hz, 2 H), 7.32–7.23 (m, 10 H), 7.19 (d, J = 8.1

Hz, 2 H), 7.17 (t, J = 8.2 Hz, 2 H), 5.95 (dq, J = 8.8, 1.3 Hz, 1 H), 5.89 (dq,

J = 8.7, 1.4 Hz, 1 H), 4.61 (dt, J = 8.8, 4.4 Hz, 1 H), 4.42 (dt, J = 8.7, 5.4

Hz, 1 H), 3.80–3.73 (m, 2 H), 3.62–3.56 (m, 2 H), 3.55 (d, J = 5.2 Hz,

OH), 3.49 (d, J = 5.3 Hz, OH), 2.89 (dd, J = 13.7, 6.0 Hz, 1 H), 2.83 (dd,

J = 13.9, 5.5 Hz, 1 H), 2.54 (dd, J = 13.9, 9.3 Hz, 1 H), 2.51 (dd, J = 13.7,

9.3 Hz, 1 H), 2.21 (octet, J = 4.7 Hz, 1 H), 2.08 (d, J = 1.3 Hz, 3 H), 2.04

(m, 1 H), 2.01 (d, J = 1.3 Hz, 3 H), 1.80 (m, 1 H), 1.75 (dtd, J = 15.3, 7.9,

4.4 Hz, 1 H), 1.66 (m, 1 H), 1.55 (ddt, J = 9.0, 6.5, 4.3 Hz, 1 H), 0.91 (s, 9

H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 143.42, 143.35, 140.80, 140.78,

137.38, 136.93, 130.46, 129.13, 128.64, 128.33, 128.28, 128.17,

128.13, 127.09, 127.01, 125.89, 125.87, 125.84, 70.60, 70.53, 62.15,

61.21, 45.27, 45.24, 36.97, 36.87, 32.40, 31.98, 25.90, 25.89, 18.25,

16.59, 16.41, –5.43, –5.46, –5.48.

IR (ATR): 3087, 3064, 3028, 2953, 2927, 2855, 1778, 1697, 1603, 1496,

1384, 1348, 1248, 1205, 1098, 1029, 834, 775, 732, 699 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 7.28 (t, J = 7.4 Hz, 4 H), 7.25 (d, J = 7.0

Hz, 2 H), 7.19 (tt, J = 5.9, 2.0 Hz, 2 H), 7.07 (d, J = 6.8 Hz, 2 H), 4.61 (ddt,

J = 9.7, 7.8, 3.1 Hz, 1 H), 4.35 (ddd, J = 7.7, 4.6, 4.4 Hz, 1 H), 4.09 (ddd,

J = 8.6, 7.9, 0.8 Hz, 1 H), 4.04, (dd, J = 9.0, 2.9 Hz, 1 H), 3.65 (dd, J = 5.9,

1.2 Hz, 1 H), 3.64 (d, J = 5.9 Hz, 1 H), 3.07 (dd, J = 13.3, 7.8 Hz, 1 H),

3.02 (dd, J = 13.5, 3.5 Hz, 1 H), 2.80 (dd, J = 13.3, 7.5 Hz, 1 H), 2.36 (dd,

J = 13.5, 9.7 Hz, 1 H), 2.05 (ddt, J = 13.6, 9.1, 6.5 Hz, 1 H), 1.71 (dtd, J =

13.7, 5.8, 4.3 Hz 1 H), 0.85 (s, 9 H), –0.01 (s, 3 H), –0.02 (s, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 175.83, 152.99, 138.79, 135.42,

130.12, 129.44, 129.34, 128.87, 128.56, 128.47, 128.31, 127.18,

126.42, 65.66, 61.41, 55.12, 41.71, 39.15, 37.67, 34.55, 25.93, 25.85,

18.27, –5.49, –5.50.

HRMS (ES+): m/z [433.2539]⁺calcd for C₂₆H₃₈O₂SiNa⁺[M + Na]⁺;

found: 433.2544.

HRMS (ES+): m/z [490.2390]⁺calcd for C₂₇H₃₇NO₄SiNa⁺[M + Na]⁺;

found: 490.2386.

(5S,E)-5-Benzyl-7-hydroxy-2-phenylhept-2-en-4-yl Benzoate (56)

Prepared according to the general benzoylation procedure using 55

(0.394 g, 0.961 mmol). The crude product mixture was placed into a

Teflon reaction vessel containing THF (10 mL), cooled to 0 °C, and

treated with HF·pyr (70% HF, 0.400 mL, 12.064 mmol) and left to sit

for 18 h at 4 °C without stirring. The reaction was quenched with aq

NaHCO₃(15 mL) and extracted with EtOAc (3 × 10 mL). The combined

organic extracts were dried (MgSO₄), and concentrated in vacuo. Puri-

fication by flash chromatography over silica gel gave 56 (0.312 g, 81%

over two steps) as a colorless oil; R_f= 0.63 (1:1 hexanes:EtOAc).

(S)-2-Benzyl-4-[(tert-butyldimethylsilyl)oxy]butanal (54)

To a Schlenk flask containing DCM (100 mL) and 53 (1.014 g, 2.17

mmol) at –78 °C was added DIBAL-H (1.15 mL, 6.50 mmol) dropwise.

The reaction mixture was stirred at –78 °C for 4 h before being

warmed to r.t. and quenched with 2 M Rochelle’s salt (100 mL) and

stirred for 3 h. The aqueous layer was extracted with DCM (3 × 50

mL). The combined organic extracts were washed with brine (50 mL),

dried (MgSO₄), and concentrated in vacuo. Purification by flash chro-

matography on silica gel gave 54 (0.358 g, 56%) as a colorless oil; R_f=

0.74 (4:1 hexanes:EtOAc).

IR (ATR): 3411, 3084, 3061, 3026, 2931, 2880, 1712, 1600, 1583, 1494,

1450, 1381, 1314, 1267, 1175, 1111, 1068, 1025, 907, 757, 730, 710,

IR (ATR): 3087, 3064, 3028, 2952, 2927, 2855, 2737, 2713, 1724, 1603,

696 cm^–1

.

1496, 1471, 1388, 1252, 1098, 1029, 987, 833, 809, 774, 730, 698 cm^–1

.

¹H NMR (CDCl₃, 500 MHz):  = 8.04 (d, J = 8.0 Hz, 4 H), 7.57 (tt, J = 7.5,

1.3 Hz, 1 H), 7.56 (tt, J = 7.4, 1.4 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 4 H), 7.39

(t, J = 7.0 Hz, 4 H), 7.35–7.27 (m, 10 H), 7.24–7.18 (m, 6 H), 6.01 (dd,

J = 9.1, 4.7 Hz, 1 H), 5.94 (dd, J = 9.2, 4.3 Hz, 1 H), 5.91 (dq, J = 9.2, 1.4

Hz, 1 H), 5.90 (dq, J = 9.2, 1.4 Hz, 1 H), 3.71 (t, J = 6.8 Hz, 4 H), 2.98 (dd,

J = 14.0, 5.8 Hz, 1 H), 2.97 (dd, J = 13.7, 6.3 Hz, 1 H), 2.70 (dd, J = 14.0,

8.5 Hz, 1 H), 2.67 (dd, J = 13.7, 8.2 Hz, 1 H), 2.45 (dddd, J = 12.6, 8.4,

6.2, 4.9 Hz, 1 H), 2.36 (dddd, J = 12.5, 8.2, 6.2, 4.6 Hz, 1 H), 2.19 (d, J =

1.3 Hz, 3 H), 2.12 (d, J = 1.2 Hz, 3 H), 1.88 (dq, J = 13.6, 6.8 Hz, 1 H),

1.87 (dq, J = 13.0, 6.9 Hz, 1 H), 1.76 (dq, J = 13.5, 6.5 Hz, 1 H) 1.66 (dq,

J = 13.2, 6.6 Hz, 1 H).

¹H NMR (CDCl₃, 500 MHz):  =  9.71 (d, J = 2.1 Hz, 1 H), 7.29 (t, J = 7.6

Hz, 2 H), 7.20 (tt, J = 6.7, 1.3 Hz, 1 H), 7.17 (d, J = 6.7 Hz, 2 H), 3.67

(ddd, J = 10.3, 6.9, 5.1 Hz, 1 H), 3.62 (ddd, J = 10.3, 6.7, 5.2 Hz, 1 H),

3.04 (dd, J = 13.4, 6.3 Hz, 1 H), 2.77 (dddt, J = 12.0, 7.6, 4.1, 2.0 Hz, 1 H),

2.71 (dd, J = 13.4, 7.7 Hz, 1 H), 1.89 (dddd, J = 14.5, 7.9, 6.7, 5.1 Hz, 1 H)

1.72 (dddd, J = 14.3, 6.8, 5.2, 4.4 Hz, 1 H), 0.87 (s, 9 H), 0.03 (s, 3 H),

0.02 (s, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 204.15, 138.87, 128.99, 128.50,

126.35, 60.48, 50.68, 34.69, 31.75, 25.86, 18.22, –5.51.

HRMS (ES+): m/z [315.1756]⁺calcd for C₁₇H₂₈O₂SiNa⁺[M + Na]⁺;

¹³C NMR (CDCl₃, 126 MHz):  = 165.87, 142.82, 142.78, 140.52,

140.25, 140.13, 132.93, 132.92, 130.46, 129.61, 129.59, 129.10,

129.05, 128.50, 128.49, 128.38, 128.25, 128.23, 127.53, 127.49,

126.17, 125.97, 125.96, 124.23, 123.86, 73.88, 73.71, 61.17, 61.13,

42.22, 41.48, 37.08, 36.92, 32.94, 32.87, 16.86, 16.69.

HRMS (ES+): m/z [423.1936]⁺calcd for C₂₇H₂₈O₃Na⁺[M + Na]⁺; found:

423.1933.

found: 315.1757.

(5S,E)-5-Benzyl-7-[(tert-butyldimethylsilyl)oxy]-2-phenylhept-2-

en-4-ol (55)

To a Schlenk flask containing Et₂O (12.0 mL) and t-BuLi (1.7 M, 2.82

mL, 4.8 mmol) at –78 °C was added vinyl iodide 27³⁰(0.190 g, 0.78

mmol) dropwise. The solution was stirred for 5 min at –78 °C, 54

(0.585g, 2.4 mmol) was then added dropwise, and the reaction was

stirred for 1 h at –78 °C. The reaction was quenched with aq NH₄Cl

(30 mL), and extracted with EtOAc (3 × 20 mL). The combined organic

extracts were dried (MgSO₄), and concentrated in vacuo. Purification

by flash chromatography on silica gel gave 55 (0.394 g, 93%) as a col-

orless oil (d.r. = 62:38); R_f= 0.44 (4:1 hexanes:EtOAc).

(3S,E)-3-Benzyl-6-phenylhept-4-en-1-ol (57)

Prepared according to the general procedure for SmI₂(H₂O)_nreduc-

tions using 56 (0.312 g, 0.786 mmol). Purification by flash chroma-

tography on silica gel gave 57 (0.13 g, 32%) as mixture of diastereo-

mers (d.r. = 74:26), R_f= 0.28 (4:1 hexanes:EtOAc).

IR (ATR): 3396, 3083, 3061, 3021, 2927, 2856, 1601, 1494, 1471, 1445,

IR (ATR): 3084, 3056, 2928, 1600, 1583, 1494, 1450, 1381, 1068, 1025,

1386, 1254, 1084, 1005, 908, 833, 775, 757, 730, 696, 664 cm^–1

.

907, 757, 696 cm^–1

.

P

T. F. Stockdale et al.

Paper

Synthesis

Major Diastereomer

(8) Prasad, E.; Flowers, R. A. II. J. Am. Chem. Soc. 2005, 127, 1299.

(9) Chopade, P. R.; Prasad, E.; Flowers, R. A. II. J. Am. Chem. Soc.

2004, 126, 44.

¹H NMR (CDCl₃, 500 MHz):  = 7.40 (d, J = 4.5 Hz, 2 H), 7.36–7.23 (m, 4

H), 7.23–7.02 (m, 4 H), 5.50 (dd, J = 15.7, 6.9 Hz, 1 H), 5.28 (ddd, J =

15.6, 9.3, 1.5 Hz, 1 H), 3.77–3.57 (m, 2 H), 3.40 (m, 1 H), 2.74 (dd, J =

13.3, 6.4 Hz, 1 H), 2.63 (dd, J = 13.5, 8.4 Hz, 1 H), 2.48 (m, 1 H), 2.24 (t,

J = 6.8 Hz, 1 H), 1.75 (dtd, J = 14.0, 7.1, 3.9 Hz, 1 H), 1.56 (m, 1 H), 1.27

(d, J = 7.0 Hz, 3 H).

¹³C NMR (CDCl₃, 126 MHz):  = 146.08, 140.91, 140.34, 136.11,

132.10, 129.42, 129.40, 129.24, 128.59, 128.34, 128.31, 128.20,

128.15, 128.11, 127.69, 127.15, 127.13, 127.01, 126.63, 126.38,

125.95, 125.92, 125.84, 125.83, 125.67, 65.40, 61.45, 61.43, 61.13,

42.54, 42.46, 42.00, 41.98, 41.74, 40.77, 37.63, 37.48, 37.37, 36.68,

32.72, 21.29, 16.10.

(10) (a) Chciuk, T. V.; Anderson, W. R.; Flowers, R. A. II. J. Am. Chem.

Soc. 2016, 138, 8738. (b) Chciuk, T. V.; Anderson, W. R.; Flowers,

R. A. II. J. Am. Chem. Soc. 2018, 140, 15342. (c) Chciuk, T. V.;

Flowers, R. A. II. J. Am. Chem. Soc. 2015, 137, 11526. (d) Kolmar,

S. S.; Mayer, J. M. J. Am. Chem. Soc. 2017, 139, 10687.

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50, 7355. (b) Volz, E. O.; O’Neil, G. W. J. Org. Chem. 2011, 76,

8428.

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W. Tetrahedron Lett. 2013, 54, 6125.

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(15) (a) Farran, H.; Hoz, S. Org. Lett. 2008, 10, 4875. (b) Maity, S.;

Flowers, R. A. II.; Hoz, S. Chem. Eur. J. 2017, 23, 17070.

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HRMS (ES+): m/z [303.1725]⁺calcd for C₂₀H₂₄ONa⁺[M + Na]⁺; found:

303.1725.

Funding Information

National Science Foundation (CHE-1760918)

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(19) Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307.

(20) The reaction was also performed using DMPU and H₂O together

and gave the same d.r. (75:25) as that obtained when using

DMPU (Table 1, entry 1) or H₂O (entry 5).

(21) Compound 6 was converted to a 1:1 mixture of diastereomers

by oxidation with Dess–Martin periodinane followed by reduc-

tion with NaBH₄. See reference 13.

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/s-0039-1690826.

S

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[Sm]

OH

Ph

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Sm-II'

Scheme 12

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Article Doi

Chelation and Stereodirecting Group Effects on Regio- And Diastereoselective Samarium(II)-Water Allylic Benzoate Reductions

DOI: 10.1055/s-0039-1690826

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Article abstract of DOI:10.1055/s-0039-1690826

Full text of DOI:10.1055/s-0039-1690826

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